PRKDC

Summary

PRKDC (protein kinase, DNA-activated, catalytic subunit, HGNC:9413) is a protein-coding gene on chromosome 8q11.21, encoding DNA-dependent protein kinase catalytic subunit (P78527). Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. In precision oncology, PRKDC Mutation confers sensitivity to Anti-PD1 Monoclonal Antibody + Anti-CTLA-4 Monoclonal Antibody in Lung Non-small Cell Carcinoma (CIViC Level B); 1 further curated variant–drug associations are listed below. It is a common-essential gene (DepMap: required in 90.5% of cancer cell lines).

This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.

Source: NCBI Gene 5591 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe combined immunodeficiency due to DNA-PKcs deficiency (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 4,961 total — 3 pathogenic, 1 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 15 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 28
• Drug target: yes — 1 curated mechanism-of-action drug; 23 molecules with ChEMBL bioactivity (top 2% of genes corpus-wide)
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer dependency (DepMap): dependent in 90.5% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.18 (highly constrained)
• MANE Select transcript: NM_006904
• Interaction hub: 4,542 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9413
Approved symbol	PRKDC
Name	protein kinase, DNA-activated, catalytic subunit
Location	8q11.21
Locus type	gene with protein product
Status	Approved
Aliases	DNPK1, p350, DNAPK, XRCC7, DNA-PKcs, DNAPKc, DNA-PKC, p460
Ensembl gene	ENSG00000253729
Ensembl biotype	protein_coding
OMIM	600899
Entrez	5591

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 18 retained_intron, 10 protein_coding

MANE Select: ENST00000314191

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 4, TSL 3: 4, TSL 4: 1

ENST00000314191, ENST00000338368, ENST00000432581, ENST00000521331, ENST00000535375, ENST00000536429, ENST00000536483, ENST00000536710, ENST00000540819, ENST00000541488, ENST00000546304, ENST00000697591, ENST00000697601, ENST00000697602, ENST00000697603, ENST00000697604, ENST00000697605, ENST00000697606, ENST00000697607, ENST00000697608, ENST00000697609, ENST00000697610, ENST00000697611, ENST00000911723, ENST00000911724, ENST00001087119, ENST00001113208, ENST00001139751

RefSeq mRNA: 2 — MANE Select: NM_006904 NM_001081640, NM_006904

CCDS: CCDS75734, CCDS75735

Canonical transcript exons

ENST00000314191 — 86 exons

Exon	Start	End
ENSE00001251756	47893139	47893387
ENSE00003463392	47904869	47904976
ENSE00003464290	47857156	47857299
ENSE00003465720	47898470	47898569
ENSE00003469129	47849154	47849303
ENSE00003469759	47881416	47881520
ENSE00003472060	47927771	47927890
ENSE00003478715	47930672	47930787
ENSE00003480320	47858516	47858635
ENSE00003481049	47915328	47915418
ENSE00003481984	47794290	47794501
ENSE00003482980	47803306	47803480
ENSE00003483488	47918277	47918383
ENSE00003486727	47858849	47858986
ENSE00003490575	47957355	47957431
ENSE00003498493	47885944	47886147
ENSE00003505958	47954338	47954446
ENSE00003507347	47935009	47935058
ENSE00003510207	47783742	47783809
ENSE00003511659	47955874	47955948
ENSE00003514268	47897161	47897294
ENSE00003528470	47860899	47860971
ENSE00003530848	47879491	47879658
ENSE00003534300	47888518	47888650
ENSE00003538011	47933965	47934090
ENSE00003538812	47778459	47778660
ENSE00003539593	47957171	47957263
ENSE00003540807	47836338	47836527
ENSE00003543221	47900373	47900467
ENSE00003546223	47782378	47782598
ENSE00003548623	47854083	47854214
ENSE00003550340	47929092	47929178
ENSE00003555327	47799210	47799390
ENSE00003555461	47839148	47839246
ENSE00003559379	47902569	47902795
ENSE00003564718	47826656	47826861
ENSE00003570797	47959973	47960136
ENSE00003571367	47933020	47933172
ENSE00003571607	47782162	47782254
ENSE00003571745	47943974	47944029
ENSE00003574154	47831814	47831926
ENSE00003574485	47785113	47785317
ENSE00003575796	47789151	47789238
ENSE00003577378	47779004	47779093
ENSE00003577697	47773111	47774377
ENSE00003582287	47855222	47855373
ENSE00003583018	47819402	47819510
ENSE00003584498	47912410	47912562
ENSE00003584655	47817450	47817561
ENSE00003585228	47820719	47820943
ENSE00003585871	47913901	47914064
ENSE00003585917	47852673	47852784
ENSE00003588109	47935732	47935900
ENSE00003591773	47953620	47953719
ENSE00003594290	47862373	47862541
ENSE00003600629	47849379	47849503
ENSE00003603195	47776844	47776983
ENSE00003606681	47864556	47864763
ENSE00003608204	47889014	47889222
ENSE00003609287	47800793	47800986
ENSE00003609866	47890257	47890480
ENSE00003609984	47778728	47778799
ENSE00003610356	47830605	47830736
ENSE00003612241	47953807	47953919
ENSE00003613407	47936353	47936517
ENSE00003614443	47927194	47927353
ENSE00003615365	47828168	47828347
ENSE00003615784	47837212	47837419
ENSE00003618540	47943853	47943883
ENSE00003619555	47929853	47930012
ENSE00003621734	47788906	47789049
ENSE00003627485	47862062	47862127
ENSE00003627756	47798237	47798397
ENSE00003628148	47840016	47840189
ENSE00003636146	47777686	47777874
ENSE00003640090	47863399	47863577
ENSE00003646863	47834196	47834396
ENSE00003651913	47877724	47877851
ENSE00003652630	47859611	47859759
ENSE00003653627	47939551	47939697
ENSE00003669434	47821604	47821792
ENSE00003674052	47943209	47943366
ENSE00003675067	47807137	47807326
ENSE00003676109	47881912	47882097
ENSE00003684631	47823858	47823996
ENSE00003691879	47887547	47887705

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.9993 / max 567.7366, expressed in 1826 samples.

Highest expression (Bgee): ventricular zone, stromal cell of endometrium, ganglionic eminence, embryo, cortical plate.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PRKDC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

16 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	9.6e-09	+0.53	8:47907696:G:A
Skin Not Sun Exposed Suprapubic	eqtl	4.1e-07	+0.61	8:46969588:G:T
Lung	eqtl	3.2e-05	+0.56	8:47112976:C:T
Thyroid	eqtl	3.4e-05	+0.46	8:47907696:G:A
Muscle Skeletal	eqtl	7.6e-04	-0.13	8:47765644:G:A
Artery Tibial	eqtl	2.1e-03	+0.32	8:47704394:G:C
Skin Sun Exposed Lower leg	eqtl	2.8e-03	+0.45	8:47019090:G:T
Stomach	eqtl	7.3e-03	+0.42	8:46969588:G:T
Adipose Subcutaneous	eqtl	9.5e-03	+0.39	8:47114752:C:T
Esophagus Muscularis	eqtl	1.1e-02	+0.33	8:46969588:G:T
Breast Mammary Tissue	eqtl	1.1e-02	+0.46	8:47112976:C:T
Brain Cortex	eqtl	1.6e-02	+0.24	8:48887552:A:C
Cells Cultured fibroblasts	eqtl	2.1e-02	+0.21	8:48128646:C:T
Artery Aorta	sqtl	2.7e-02	-1.10	8:47117793:G:A
Prostate	eqtl	3.7e-02	-0.30	8:48736569:TGACAA:T
Artery Aorta	eqtl	4.5e-02	+0.39	8:47734144:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
92988	79.4136	1826
92986	0.3588	185
92974	0.2269	56

Top tissues by expression

showing 100 of 303 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.64	gold quality
stromal cell of endometrium	CL:0002255	97.52	gold quality
ganglionic eminence	UBERON:0004023	97.23	gold quality
embryo	UBERON:0000922	97.21	gold quality
cortical plate	UBERON:0005343	95.81	gold quality
colonic epithelium	UBERON:0000397	94.57	gold quality
adrenal tissue	UBERON:0018303	94.44	gold quality
oral cavity	UBERON:0000167	94.43	gold quality
left uterine tube	UBERON:0001303	94.02	gold quality
ectocervix	UBERON:0012249	93.98	gold quality
endometrium epithelium	UBERON:0004811	93.75	gold quality
right ovary	UBERON:0002118	93.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.37	gold quality
penis	UBERON:0000989	93.34	gold quality
pigmented layer of retina	UBERON:0001782	93.32	gold quality
retina	UBERON:0000966	93.30	gold quality
body of uterus	UBERON:0009853	93.26	gold quality
skin of leg	UBERON:0001511	93.21	gold quality
left ovary	UBERON:0002119	92.87	gold quality
skin of abdomen	UBERON:0001416	92.77	gold quality
esophagus mucosa	UBERON:0002469	92.73	gold quality
right testis	UBERON:0004534	92.68	gold quality
zone of skin	UBERON:0000014	92.58	gold quality
prefrontal cortex	UBERON:0000451	92.43	gold quality
esophagus	UBERON:0001043	92.40	gold quality
endocervix	UBERON:0000458	92.36	gold quality
gastrocnemius	UBERON:0001388	92.34	gold quality
bone marrow cell	CL:0002092	92.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.26	gold quality
vagina	UBERON:0000996	92.25	gold quality
muscle of leg	UBERON:0001383	92.24	gold quality
left testis	UBERON:0004533	92.16	gold quality
lower esophagus	UBERON:0013473	92.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.05	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.00	gold quality
skin of hip	UBERON:0001554	91.98	gold quality
sigmoid colon	UBERON:0001159	91.91	gold quality
calcaneal tendon	UBERON:0003701	91.89	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.82	gold quality
pituitary gland	UBERON:0000007	91.81	gold quality
right coronary artery	UBERON:0001625	91.81	gold quality
mammalian vulva	UBERON:0000997	91.76	gold quality
testis	UBERON:0000473	91.75	gold quality
seminal vesicle	UBERON:0000998	91.75	gold quality
right adrenal gland cortex	UBERON:0035827	91.73	gold quality
right adrenal gland	UBERON:0001233	91.72	gold quality
myometrium	UBERON:0001296	91.70	gold quality
spleen	UBERON:0002106	91.70	gold quality
upper lobe of left lung	UBERON:0008952	91.69	gold quality
nerve	UBERON:0001021	91.66	gold quality
tibial nerve	UBERON:0001323	91.66	gold quality
ovary	UBERON:0000992	91.53	gold quality
upper lobe of lung	UBERON:0008948	91.52	gold quality
endometrium	UBERON:0001295	91.51	gold quality
left coronary artery	UBERON:0001626	91.49	gold quality
pharyngeal mucosa	UBERON:0000355	91.45	gold quality
adenohypophysis	UBERON:0002196	91.39	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.34	gold quality
colonic mucosa	UBERON:0000317	91.32	gold quality
right frontal lobe	UBERON:0002810	91.30	gold quality
minor salivary gland	UBERON:0001830	91.27	gold quality
adipose tissue	UBERON:0001013	91.26	gold quality
coronary artery	UBERON:0001621	91.26	gold quality
body of stomach	UBERON:0001161	91.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.22	gold quality
body of pancreas	UBERON:0001150	91.21	gold quality
connective tissue	UBERON:0002384	91.21	gold quality
left adrenal gland	UBERON:0001234	91.20	gold quality
peritoneum	UBERON:0002358	91.15	gold quality
uterus	UBERON:0000995	91.14	gold quality
omental fat pad	UBERON:0010414	91.14	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.13	gold quality
popliteal artery	UBERON:0002250	91.11	gold quality
tibial artery	UBERON:0007610	91.11	gold quality
artery	UBERON:0001637	91.10	gold quality
adrenal gland	UBERON:0002369	91.10	gold quality
stomach	UBERON:0000945	91.08	gold quality
superior surface of tongue	UBERON:0007371	91.08	gold quality
colon	UBERON:0001155	91.04	gold quality
aorta	UBERON:0000947	91.03	gold quality
transverse colon	UBERON:0001157	91.03	gold quality
female reproductive system	UBERON:0000474	91.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.01	gold quality
ascending aorta	UBERON:0001496	90.98	gold quality
urinary bladder	UBERON:0001255	90.97	gold quality
right uterine tube	UBERON:0001302	90.96	gold quality
thoracic aorta	UBERON:0001515	90.94	gold quality
large intestine	UBERON:0000059	90.91	gold quality
left adrenal gland cortex	UBERON:0035825	90.88	gold quality
intestine	UBERON:0000160	90.86	gold quality
synovial joint	UBERON:0002217	90.85	gold quality
right lobe of thyroid gland	UBERON:0001119	90.83	gold quality
frontal cortex	UBERON:0001870	90.82	gold quality
frontal lobe	UBERON:0016525	90.82	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.77	gold quality
cauda epididymis	UBERON:0004360	90.72	gold quality
tonsil	UBERON:0002372	90.68	gold quality
islet of Langerhans	UBERON:0000006	90.66	gold quality
adrenal cortex	UBERON:0001235	90.62	gold quality
mucosa of transverse colon	UBERON:0004991	90.61	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	4909.79
E-MTAB-6386	no	2773.52
E-CURD-10	no	367.74
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	45.8
Nucleus accumbens	tissue	43.8
Locus coeruleus	tissue	42.3
Postcentral gyrus	tissue	39.6
Hippocampus	tissue	38.5	high
Thymus	tissue	28.6
Retina	tissue	22.6
Bone marrow	tissue	17.7	high
Vagina	tissue	17.0	high
Lymph node	tissue	16.3	high
Pituitary gland	tissue	15.5
Tonsil	tissue	15.5	high
Tongue	tissue	15.4
Appendix	tissue	14.9	high
Parathyroid gland	tissue	14.1	high
Skin 1	tissue	13.4	high
Testis	tissue	13.2	high
Breast	tissue	12.9	high
Skeletal muscle	tissue	12.8	high
Thyroid gland	tissue	12.2	high
Urinary bladder	tissue	11.9	high
Smooth muscle	tissue	11.4	medium
Colon	tissue	11.2	high
Adipose tissue	tissue	11.1	high
Spleen	tissue	11.1	high
Rectum	tissue	10.9	high
Pancreas	tissue	10.8	high
Ovary	tissue	10.7	high
Endometrium 1	tissue	10.7	high
Placenta	tissue	10.5	high
Cervix	tissue	10.3	high
Prostate	tissue	9.5	high
Esophagus	tissue	9.3	high
Stomach 1	tissue	9.0	high
Hippocampal formation	tissue	9.0
Amygdala	tissue	8.8
Seminal vesicle	tissue	8.7	high
Ventral forebrain	tissue	8.7
Cerebellum	tissue	8.6	high
Fallopian tube	tissue	8.6	high
Cerebral cortex	tissue	8.5	high
Insular cortex	tissue	8.5
Heart muscle	tissue	8.4	high
Salivary gland	tissue	8.0	high
Basal ganglia	tissue	8.0	high
Hypothalamus	tissue	8.0
Septum	tissue	8.0
Temporal cortex	tissue	8.0
Putamen	tissue	7.9
Retrosplenial cortex	tissue	7.9
Kidney	tissue	7.8	high
Liver	tissue	7.7	medium
Entorhinal cortex	tissue	7.7
Retrosplenial and cingulate cortex	tissue	7.7
Occipital cortex	tissue	7.7
Prefrontal cortex	tissue	7.6
Motor cortex	tissue	7.6
Somatosensory cortex	tissue	7.6
Gallbladder	tissue	7.5	high
Corpus callosum	tissue	7.5

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Corpus callosum, splenium (white matter) (50.9), Corpus callosum, genu (white matter) (50.8), Parieto-temporal junction (white matter) (49.9), Lateral funiculus (white matter) (48.4), Occipital cortex (white matter) (47.4).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets:

Target	Regulation
GREB1
ITGB4
PREX1
ROCK2
UGT2B17

Upstream regulators (CollecTRI, top): AP1, E2F1, ESR1, JUN, MYC, PRDM1

miRNA regulators (miRDB)

Targeting PRKDC by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 54 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.183, missense Z 2.46 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000314191 splits into 6 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
8:47,774,176–47,799,371	706 / 945.0	0.75	no
8:47,799,372–47,862,391	1592 / 1724.6	0.92	no
8:47,862,392–47,864,560	80 / 132.3	0.60	no
8:47,864,561–47,954,443	1969 / 2068.9	0.95	no
8:47,954,444–47,957,175	12 / 31.1	0.39	no
8:47,957,176–47,960,126	145 / 136.3	1.06	no
DepMap (CRISPR cell-line fitness): dependent in 90.5% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): CH-157MN (-1.973), NCI-H23 (-1.887), NOMO-1 (-1.838), T-47D (-1.74), MOLM-13 (-1.659), UM-HACC-2A (-1.628), KP-N-SI9s (-1.616), NRH-OS4 (-1.512), TALL-1 (-1.401), NB-1 (-1.397), YCUB-2 (-1.351), D458 (-1.326), GCT-27 (-1.322), NRH-LS3 (-1.295), ZR-75-1 (-1.291).

Literature-anchored findings (GeneRIF, showing 40)

• role for DNA-PK in regulating IRF-3 activity (PMID:11867762)
• DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination (PMID:11904432)
• Roles of DNA-dependent protein kinase and ATM in cell-cycle-dependent radiation sensitivity in human cells. (PMID:12065055)
• results suggest that DNA-PK(CS) brings DNA ends together and then undergoes activation of its kinase, presumably to regulate subsequent steps for processing and ligation of the ends (PMID:12065431)
• phosphorylation at Thr2609, Ser2612, Thr2638 and Thr2647 may play an important role in DNA-PK function. (PMID:12186630)
• DNA-PKcs is autophosphorylated at Thr2609 in vivo in a Ku-dependent manner in response to ionizing radiation (PMID:12231622)
• Autophosphorylation of DNA-PK plays an important regulatory role in DNA double-strand break repair by regulating the assembly and disassembly of the DNA-PK-DNA complex. (PMID:12379113)
• Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment (PMID:12547193)
• DNA-PKcs subunit and holoenzyme has a role in the signal transduction of ionizing radiation response (PMID:12672807)
• Chk1 and DNA-PK complex proteins have a role in the repair of double strand breaks (PMID:12756247)
• Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair (PMID:12897153)
• up-regulation of DNA-PK complex protein, especially DNA-PKcs, after radiation treatment correlates to radiation resistance (PMID:14556663)
• DNA-PK can be activated by nucleosomes through the ability of Ku to bind to the ends of nucleosomal DNA, and that the activated DNA-PK is capable of phosphorylating H2AX within the nucleosomes (PMID:14627815)
• working model in which DNA-PK creates a stable molecular bridge between two DNA ends that is remodeled after DNA-PK autophosphorylation (PMID:14654699)
• DNA-PK phosphorylated recombinant NDH II in the presence of RNA (PMID:14704337)
• protein phosphatase 5 interacts with DNA-PKcs and dephosphorylates with surprising specificity at least two functional sites. (PMID:14734805)
• evidence that DNA-PK inhibits AAV integration both in vitro and in vivo (PMID:14766968)
• Data describe a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor kappaB (NF-kappaB) activation and chemoresistance in response to DNA damage. (PMID:14966265)
• Results show that Ku70/Ku80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) modulate RAG-mediated cleavage during V(D)J recombination. (PMID:15123719)
• cleaved by picornain 2A during poliovirus infection of HeLa cells (PMID:15163725)
• Autophosphorylation at ABCDE sites thus apparently directs a rearrangement of the DNA-PK complex that ensures access to broken ends and joining steps are coupled together within a synaptic complex, making repair more accurate. (PMID:15258142)
• DNA-PK has a role in the Ser-473 phosphorylation step in the activation of PKB (PMID:15262962)
• DNA-PK has roles in the cellular response to DNA double-strand breaks [review] (PMID:15279776)
• Inhibition of PARP-1 and DNA-dependent protein kinase id a powerful strategy for tumor radiosensitization. (PMID:15286704)
• reduced, not depleted expression of DNA-PK during the mature stages of myeloid differentiation (PMID:15353130)
• DNA-PK autophosphorylation is regulated by MDC1 in response to DNA damage (PMID:15377652)
• These results collectively suggested two pathways for IR-induced phosphorylation of Ser46, i.e., direct phosphorylation by DNA-PK and indirect phosphorylation via ATM. (PMID:15381073)
• DNA-PK, ATM and possibly other kinases implicated in H2AX phosphorylation. (PMID:15389585)
• DNA-PK has a positive role in the regulation of apoptosis in human glioblastomas. (PMID:15493013)
• DNAPK was physically required for the mobilization of the XRCC4-ligase IV complex, and for stable recruitment of XRCC4; phosphorylation of either H2AX or XRCC4 was unnecessary for DNAPK or XRCC4-ligase IV recruitment (PMID:15520013)
• DNA-PK augments ATM and ATR in activation of Chk2 by DNA damage. (PMID:15668230)
• Conserved splice variants of a catalytic subunit of DNA-PK (DNA-PKcs) are expressed predominately in nondividing cells (PMID:15668400)
• DNA-PKcs is preferentially activated by the physiologically relevant DNA replication-associated DSBs at the sites of DNA synthesis (PMID:15677476)
• Using cryo-electron microscopy there was generated an approximately 13 A three-dimensional map of DNA-PKcs, revealing the overall architecture and topology of the 4128 residue polypeptide chain and allowing location of domains (PMID:15698568)
• identification of related, conserved carboxy-terminal motifs in human Nbs1, ATRIP and Ku80 proteins that are required for their interaction with ATM, ATR and DNA-PKcs, respectively (PMID:15758953)
• Artemis:DNA-PKcs nuclease may be important in removing secondary structures that hinder processing of DNA ends during nonhomologous DNA end joining . (PMID:15936993)
• Data show that blockade of epidermal growth factor receptor import into the nucleus also blocks radiation-induced activation of DNA-PK, inhibits DNA repair, and increases radiosensitivity of treated cells. (PMID:16000298)
• Significantly lower DNA-PK activity is associated with uterine cervix and breast cancer (PMID:16000400)
• caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132 (PMID:16001975)
• DNA-PK activity is required for the increased expression of H2AX in iradiated cells under hypertonic conditions. (PMID:16046194)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkdc	ENSDARG00000075083
mus_musculus	Prkdc	ENSMUSG00000022672
rattus_norvegicus	Prkdc	ENSRNOG00000025028

Paralogs (5): ATM (ENSG00000149311), SMG1 (ENSG00000157106), ATR (ENSG00000175054), TRRAP (ENSG00000196367), MTOR (ENSG00000198793)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:104779) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 153 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased CD8-positive, alpha-beta T cell number	10
decreased B cell number	8
decreased CD4-positive, alpha-beta T cell number	8
decreased IgG level	5
decreased lymphocyte cell number	5
decreased T cell number	5
increased effector memory CD4-positive, alpha-beta T cell number	5
spleen hypoplasia	4
arrested B cell differentiation	4
increased cellular sensitivity to gamma-irradiation induced cell death	4
increased T cell derived lymphoma incidence	4
premature death	4
abnormal spleen white pulp morphology	4
decreased B-1 B cell number	4
increased NK cell number	4
increased CD4-positive, alpha-beta T cell number	4
decreased CD8-positive, naive alpha-beta T cell number	4
increased neutrophil cell number	3
decreased leukocyte cell number	3
abnormal thymus morphology	3
small thymus	3
decreased IgM level	3
abnormal B cell differentiation	3
abnormal T cell differentiation	3
abnormal lymph node morphology	3

+128 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Canis lupus familiaris	Q8WN22	83.1%	Diamond
Gallus gallus	Q8QGX4	68.9%	Diamond
Saccharomyces cerevisiae S288C	P35169	68.3%	Diamond
Xenopus laevis	Q9DEI1	66.7%	Diamond
Aspergillus fumigatus Af293	Q4WVM7	65.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SPIDR	protein-coding	23514
MCM4	protein-coding	4173
CEBPD	protein-coding	1052
UBE2V2-AS1	ncRNA	105375819
UBE2V2	protein-coding	7336

Protein

Protein identifiers

DNA-dependent protein kinase catalytic subunit — P78527 (reviewed: P78527)

Alternative names: DNPK1, Ser-473 kinase, p460

All UniProt accessions (4): P78527, A0A8V8TMR1, F5GX40, H0YG84

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). Recruited by XRCC5 and XRCC6 to DNA ends and is required to (1) protect and align broken ends of DNA, thereby preventing their degradation, (2) and sequester the DSB for repair by NHEJ. Acts as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. As part of the DNA-PK complex, involved in the early steps of ribosome assembly by promoting the processing of precursor rRNA into mature 18S rRNA in the small-subunit processome. Binding to U3 small nucleolar RNA, recruits PRKDC and XRCC5/Ku86 to the small-subunit processome. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates ‘Ser-139’ of histone variant H2AX, thereby regulating DNA damage response mechanism. Phosphorylates ASF1A, DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, FH, SRF, NHEJ1/XLF, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Acts as a regulator of the phosphatidylinositol 3-kinase/protein kinase B signal transduction by mediating phosphorylation of ‘Ser-473’ of protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), promoting their activation. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 ‘Ser-588’ and increasing CRY1 protein stability, most likely through an indirect mechanism. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. Also regulates the cGAS-STING pathway by catalyzing phosphorylation of CGAS, thereby impairing CGAS oligomerization and activation. Also regulates the cGAS-STING pathway by mediating phosphorylation of PARP1.

Subunit / interactions. DNA-PK is a heterotrimer of PRKDC and the Ku dimer (composed of XRCC6/Ku70 and XRCC5/Ku86). Formation of this complex may be promoted by interaction with ILF3. Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Additional component of the NHEJ complex includes PAXX. Following autophosphorylation, PRKDC dissociates from DNA. Interacts with DNA-PKcs-interacting protein (KIP) with the region upstream the kinase domain. PRKDC alone also interacts with and phosphorylates DCLRE1C, thereby activating the latent endonuclease activity of this protein. Interacts with C1D. Interacts with TTI1 and TELO2. Interacts with CIB1. Interacts with SETX. Interacts with NR4A3; the DNA-dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitination and degradation. Interacts with BRAT1. Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA. Interacts with KAT5.

Subcellular location. Nucleus. Nucleolus. Cytoplasm. Cytosol.

Post-translational modifications. Autophosphorylated at two clusters, the T2609 cluster and the S2056 cluster. Autophosphorylated on Ser-2056, Thr-2609, Thr-2638 and Thr-2647. Ser-2056 and Thr-2609 are DNA damage-inducible phosphorylation sites (inducible with ionizing radiation, IR) dephosphorylated by PPP5C. Autophosphorylation induces a conformational change that leads to remodeling of the DNA-PK complex, requisite for efficient end processing and DNA repair. Autophosphorylation in trans within DNA-PK complexes loaded on DNA ends leads to the dissociation of PRKDC from DNA and the transition into the short-range NHEJ complex. Autophosphorylation of the T2609 cluster is required for hematopoietic development and protein synthesis in erythrocytes precursors. S-nitrosylated by GAPDH. Polyubiquitinated by RNF144A, leading to proteasomal degradation.

Disease relevance. Immunodeficiency 26 with or without neurologic abnormalities (IMD26) [MIM:615966] A form of severe combined immunodeficiency characterized by reduced or absent T and B cells, recurrent candidiasis, and lower respiratory tract infections. Some patients show dysmorphic features, severe growth failure, microcephaly, seizures, and impaired neurological functions. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activity seems to be attenuated by autophosphorylation. Binding to the SL1 region of U3 small nucleolar RNA promotes auto-phosphorylation activity. Inhibited by wortmannin.

Similarity. Belongs to the PI3/PI4-kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P78527-1	1	yes
P78527-2	2

RefSeq proteins (2): NP_001075109, NP_008835* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000403	PI3/4_kinase_cat_dom	Domain
IPR003151	PIK-rel_kinase_FAT	Domain
IPR003152	FATC_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR012582	DNAPKcs_CC3	Domain
IPR014009	PIK_FAT	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018936	PI3/4_kinase_CS	Conserved_site
IPR036940	PI3/4_kinase_cat_sf	Homologous_superfamily
IPR037706	DNA-PK_dom	Domain
IPR045581	DNAPKcs_CC5	Domain
IPR046803	DNAPKcs_CC1-2	Domain
IPR046804	DNA-PKcs_N	Domain
IPR050517	DDR_Repair_Kinase	Family

Pfam: PF00454, PF02259, PF02260, PF08163, PF19704, PF20500, PF20502

Enzyme classification (BRENDA)

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea)

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (534 total): helix 249, strand 106, turn 77, sequence variant 44, modified residue 26, region of interest 9, sequence conflict 6, mutagenesis site 6, repeat 5, domain 3, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

showing 30 of 51 structures by resolution:

PDB	Title	Method	Resolution (Å)
7Z87	DNA-PK in the active state	ELECTRON MICROSCOPY	2.91
7OTY	DNA-PKcs in complex with M3814	ELECTRON MICROSCOPY	2.96
7OTW	DNA-PKcs in complex with AZD7648	ELECTRON MICROSCOPY	2.99
7SGL	DNA-PK complex of DNA end processing	ELECTRON MICROSCOPY	3
7K11	CryoEM structure of inactivated-form FATKIN domain of DNA-PK	ELECTRON MICROSCOPY	3.21
6ZFP	Cryo-EM structure of DNA-PKcs (State 2)	ELECTRON MICROSCOPY	3.24
7OTV	DNA-PKcs in complex with wortmannin	ELECTRON MICROSCOPY	3.24
7K10	CryoEM structure of activated-form FATKIN domain of DNA-PK	ELECTRON MICROSCOPY	3.3
7SU3	CryoEM structure of DNA-PK complex VII	ELECTRON MICROSCOPY	3.3
7OTM	Cryo-EM structure of DNA-PKcs in complex with NU7441	ELECTRON MICROSCOPY	3.33
7TYR	Cryo-EM structure of the basal state of the Artemis:DNA-PKcs complex (see COMPND 13/14)	ELECTRON MICROSCOPY	3.33
7Z88	DNA-PK in the intermediate state	ELECTRON MICROSCOPY	3.33
7OTP	DNA-PKcs in complex with ATPgammaS-Mg	ELECTRON MICROSCOPY	3.4
8RD4	Telomeric RAP1:DNA-PK complex	ELECTRON MICROSCOPY	3.58
7SUD	CryoEM structure of DNA-PK complex VIII	ELECTRON MICROSCOPY	3.6
6ZH4	Cryo-EM structure of DNA-PKcs (State 3)	ELECTRON MICROSCOPY	3.62
7K0Y	Cryo-EM structure of activated-form DNA-PK (complex VI)	ELECTRON MICROSCOPY	3.7
9ZOB	CryoEM structure of DNA-PK bound to N7 nucleosome, state 2	ELECTRON MICROSCOPY	3.8
9ZP9	CryoEM structure of DNA-PK bound to N7 nucleosome, state 1	ELECTRON MICROSCOPY	3.88
7K1J	CryoEM structure of inactivated-form DNA-PK (Complex III)	ELECTRON MICROSCOPY	3.9
7K1N	CryoEM structure of inactivated-form DNA-PK (Complex V)	ELECTRON MICROSCOPY	3.9
6ZHA	Cryo-EM structure of DNA-PK monomer	ELECTRON MICROSCOPY	3.91
6ZH2	Cryo-EM structure of DNA-PKcs (State 1)	ELECTRON MICROSCOPY	3.92
6ZH6	Cryo-EM structure of DNA-PKcs:Ku80ct194	ELECTRON MICROSCOPY	3.93
9ZNC	CryoEM structure of the DNA-PK complex bound to N20 nucleosome	ELECTRON MICROSCOPY	3.93
9IAX	DNA-PK, LX4, XLF - Catalytic domain of L4	ELECTRON MICROSCOPY	3.97
7K1K	CryoEM structure of inactivated-form DNA-PK (Complex IV)	ELECTRON MICROSCOPY	4.1
9ZP0	CryoEM structure of DNA-PK bound to N0 nucleosome	ELECTRON MICROSCOPY	4.11
6ZH8	Cryo-EM structure of DNA-PKcs:DNA	ELECTRON MICROSCOPY	4.14
7NFC	Cryo-EM structure of NHEJ super-complex (dimer)	ELECTRON MICROSCOPY	4.14

Predicted structure (AlphaFold)

No AlphaFold model available for P78527 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Atypical kinases, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets, Human disease related genes, Primary immunodeficiency, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH supported · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
2020–2021	cleavage; by caspase-3

Post-translational modifications (26)

Type	Positions
N6-acetyllysine	117, 828, 1209, 1970, 2259, 3241, 3260, 3621, 3638, 3642
Phosphoserine	511, 687, 841, 893, 1065, 2056, 2612, 2789, 3205, 3731, 3821, 4026
Phosphothreonine	2535, 2609, 2638, 2647

Mutagenesis-validated functional residues (6)

Position	Phenotype
1510	loss of interaction with c1d.
1516–1517	loss of interaction with c1d.
2609	leads to radiation sensitivity and impaired dsb joining. gives rise to reduced phosphorylation; when associated with a-2612.
2612	reduced phosphorylation; when associated with a-2609.
2638	alleviates phosphorylation, leaves a fully active enzyme with compromised cellular resistance to ionizing radiation without affecting dna …
2647	alleviates phosphorylation, leaves a fully active enzyme with compromised cellular resistance to ionizing radiation without affecting dna …

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA	curated
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins	curated
R-HSA-3270619	IRF3-mediated induction of type I IFN	curated
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)	curated
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-8852135	Protein ubiquitination	—
R-HSA-1834941	STING mediated induction of host immune responses	—

MSigDB gene sets: 618 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, E2F_Q4_01, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT

GO Biological Process (38): maturation of 5.8S rRNA (GO:0000460), telomere maintenance (GO:0000723), negative regulation of protein phosphorylation (GO:0001933), activation of innate immune response (GO:0002218), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), telomere capping (GO:0016233), peptidyl-serine phosphorylation (GO:0018105), peptidyl-threonine phosphorylation (GO:0018107), mitotic G1 DNA damage checkpoint signaling (GO:0031571), cellular response to insulin stimulus (GO:0032869), immunoglobulin V(D)J recombination (GO:0033152), small-subunit processome assembly (GO:0034462), protein modification process (GO:0036211), regulation of circadian rhythm (GO:0042752), negative regulation of apoptotic process (GO:0043066), innate immune response (GO:0045087), positive regulation of lymphocyte differentiation (GO:0045621), positive regulation of erythrocyte differentiation (GO:0045648), positive regulation of translation (GO:0045727), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511), regulation of smooth muscle cell proliferation (GO:0048660), regulation of epithelial cell proliferation (GO:0050678), double-strand break repair via alternative nonhomologous end joining (GO:0097681), negative regulation of cGAS/STING signaling pathway (GO:0160049), regulation of hematopoietic stem cell differentiation (GO:1902036), positive regulation of platelet formation (GO:1905221), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034), immune system process (GO:0002376), DNA repair (GO:0006281), DNA recombination (GO:0006310), chromatin remodeling (GO:0006338), ribosome biogenesis (GO:0042254), regulation of cellular response to stress (GO:0080135)

GO Molecular Function (17): double-stranded DNA binding (GO:0003690), RNA binding (GO:0003723), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), DNA-dependent protein kinase activity (GO:0004677), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), U3 snoRNA binding (GO:0034511), histone H2AXS139 kinase activity (GO:0035979), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), DNA binding (GO:0003677), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (13): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytosol (GO:0005829), DNA-dependent protein kinase-DNA ligase 4 complex (GO:0005958), membrane (GO:0016020), small-subunit processome (GO:0032040), protein-containing complex (GO:0032991), protein-DNA complex (GO:0032993), nonhomologous end joining complex (GO:0070419)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Innate Immune System	1
STING mediated induction of host immune responses	1
DNA Double-Strand Break Repair	1
Protein ubiquitination	1
Immune System	1
Cytosolic sensors of pathogen-associated DNA	1
DNA Repair	1
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

showing 60 of 70 GO namespaces:

Category	Terms
cellular anatomical structure	4
protein phosphorylation	3
nucleic acid binding	2
protein kinase activity	2
protein serine/threonine kinase activity	2
protein binding	2
nuclear lumen	2
protein-containing complex	2
nuclear protein-containing complex	2
rRNA processing	1
DNA metabolic process	1
telomere organization	1
regulation of protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
activation of immune response	1
positive regulation of innate immune response	1
DNA repair	1
double-strand break repair	1
phosphorylation	1
protein modification process	1
cellular response to stress	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
telomere maintenance	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
response to insulin	1
cellular response to peptide hormone stimulus	1
somatic recombination of immunoglobulin gene segments	1
V(D)J recombination	1
protein-RNA complex assembly	1
cytosolic small ribosomal subunit assembly	1
protein metabolic process	1
macromolecule modification	1
circadian rhythm	1
regulation of biological process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
immune response	1
defense response to symbiont	1
DNA binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
snoRNA binding	1
histone H2AX kinase activity	1
DNA-binding transcription factor binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
chromosomal region	1
chromosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 38 of 68 annotations. The rest are phylogenetic / computational / electronic (IEA).

38 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
activation of innate immune response	BP	direct assay
cellular response to insulin stimulus	BP	mutant phenotype
double-strand break repair	BP	mutant phenotype
maturation of 5.8S rRNA	BP	direct assay
mitotic G1 DNA damage checkpoint signaling	BP	mutant phenotype
negative regulation of apoptotic process	BP	mutant phenotype
negative regulation of cGAS/STING signaling pathway	BP	direct assay
peptidyl-serine phosphorylation	BP	direct assay
peptidyl-threonine phosphorylation	BP	direct assay
positive regulation of double-strand break repair via nonhomologous end joining	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	mutant phenotype
protein phosphorylation	BP	direct assay
regulation of epithelial cell proliferation	BP	mutant phenotype
regulation of smooth muscle cell proliferation	BP	mutant phenotype
small-subunit processome assembly	BP	direct assay
telomere capping	BP	mutant phenotype
DNA-dependent protein kinase-DNA ligase 4 complex	CC	direct assay
chromatin	CC	direct assay
chromosome, telomeric region	CC	high-throughput assay
membrane	CC	high-throughput assay
nonhomologous end joining complex	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
protein-DNA complex	CC	direct assay
protein-containing complex	CC	mutant phenotype
small-subunit processome	CC	direct assay
transcription regulator complex	CC	direct assay
DNA-dependent protein kinase activity	MF	direct assay
RNA binding	MF	high-throughput assay
RNA polymerase II-specific DNA-binding transcription factor binding	MF	physical interaction
U3 snoRNA binding	MF	direct assay
double-stranded DNA binding	MF	direct assay
histone H2AXS139 kinase activity	MF	direct assay
protein domain specific binding	MF	physical interaction
protein kinase activity	MF	direct assay
protein serine/threonine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 4,542 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKDC	XRCC5	P13010	969
PRKDC	XRCC6	P12956	968
PRKDC	XRCC4	Q13426	958
PRKDC	LIG4	P49917	928
PRKDC	NHEJ1	Q9H9Q4	928
PRKDC	RAD50	Q92878	871
PRKDC	CHEK1	O14757	862
PRKDC	ATRIP	Q8WXE1	852
PRKDC	H2AX	P16104	833
PRKDC	BRCA1	P38398	832
PRKDC	RPA2	P15927	815
PRKDC	CHEK2	O96017	811
PRKDC	TP53BP1	Q12888	805
PRKDC	FANCD2	Q9BXW9	789
PRKDC	STN1	Q9H668	765
PRKDC	DCLRE1C	Q96SD1	765

IntAct

Human interaction partners of PRKDC in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 61 partners by confidence:

Partner	Interaction type	MIscore	Records
XRCC6	physical association	0.900	5
XRCC5	direct interaction	0.900	2
DCLRE1C	physical association	0.700	2
PARP1	association	0.640	2
TELO2	association	0.600	1
NR1H4	physical association	0.560	1
ETS1	direct interaction	0.520	1
ETV1	direct interaction	0.520	1
SPI1	direct interaction	0.520	1
AR	physical association	0.500	3
AIRE	association	0.500	2
HOXB7	physical association	0.500	1
MAPKAP1	physical association	0.500	1
RARA	physical association	0.500	1
YY1	physical association	0.500	1
EGFR	proximity	0.480	1
NOTCH1	association	0.460	1
ERG	direct interaction	0.440	1
ZIC2	phosphorylation reaction	0.440	1
DBP	colocalization	0.430	1
IGFBP3	proximity	0.420	1
YWHAG	physical association	0.400	2
ANXA2	physical association	0.400	1
CDK8	physical association	0.400	1
CHD1L	physical association	0.400	1
CPN1	physical association	0.400	1
DEAF1	physical association	0.400	1
FAM161A	physical association	0.400	1
GTPBP4	physical association	0.400	1
KIAA1217	physical association	0.400	1

BioGRID (1,176 interactions; top human partners by supporting records in a sample of 600 records): XRCC5 (Co-fractionation; 13 records), XRCC6 (Affinity Capture-MS; 10 records), TP53 (Biochemical Activity; 9 records), TOP1 (Affinity Capture-MS; 7 records), HIF1A (Affinity Capture-Western; 6 records), BRCA1 (Protein-peptide; 5 records), DCLRE1C (Affinity Capture-MS; 5 records), RNF144A (Affinity Capture-Western; 5 records), ATM (Protein-peptide; 4 records), C1D (Two-hybrid; 4 records), ILF2 (Affinity Capture-MS; 4 records), RPA2 (Biochemical Activity; 4 records), ARAF (Affinity Capture-MS; 3 records), CDC5L (Affinity Capture-MS; 3 records), CDK9 (Negative Genetic; 3 records)

SIGNOR signaling

showing 45 of 87 signaling interactions:

A	Effect	B	Mechanism
PRKDC	up-regulates	IRF3	phosphorylation
PRKDC	up-regulates	RPA2	phosphorylation
PRKDC	unknown	RPA2	phosphorylation
PRKDC	down-regulates	LIG4	phosphorylation
PRKDC	up-regulates	CHEK2	phosphorylation
PRKDC	up-regulates	DCLRE1C	phosphorylation
ATR	up-regulates	PRKDC	phosphorylation
ATM	up-regulates	PRKDC	phosphorylation
PRKDC	up-regulates	PRKDC	phosphorylation
PRKDC	down-regulates	PRKDC	phosphorylation
PRKDC	up-regulates	PNKP	phosphorylation
PRKDC	unknown	NHEJ1	phosphorylation
XRCC6	up-regulates	PRKDC	relocalization
PRKDC	up-regulates	CASP2	phosphorylation
PRKDC	up-regulates	USF1	phosphorylation
PRKDC	up-regulates	HNRNPU	phosphorylation
PRKDC	up-regulates	TDP1	phosphorylation
PRKDC	up-regulates	H2AX	phosphorylation
8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one	down-regulates	PRKDC	“chemical inhibition”
PRKDC	up-regulates	WRN	phosphorylation
PI-103	down-regulates	PRKDC	“chemical inhibition”
“PIK-75 Hydrochloride”	down-regulates	PRKDC	“chemical inhibition”
PP121	down-regulates	PRKDC	“chemical inhibition”
PRKDC	“form complex”	DNA-PK	binding
HOXB7	“up-regulates activity”	PRKDC	binding
PRKDC	unknown	HSP90AA1	phosphorylation
PRKDC	“up-regulates activity”	PRKDC	phosphorylation
PRKDC	“up-regulates activity”	AKT1	phosphorylation
PRKDC	“up-regulates activity”	AKT	phosphorylation
PRKDC	“up-regulates activity”	PNPT1	phosphorylation
RNF144A	“down-regulates quantity by destabilization”	PRKDC	polyubiquitination
PRKDC	“up-regulates activity”	MCC	phosphorylation
PRKDC	“down-regulates activity”	H1-2	phosphorylation
PRKDC	“up-regulates activity”	POLL	phosphorylation
PRKDC	“up-regulates activity”	XRCC6	phosphorylation
CTDSP1	“up-regulates activity”	PRKDC	dephosphorylation
PPP6C	“up-regulates activity”	PRKDC	dephosphorylation
PRKDC	“up-regulates activity”	XRCC4	phosphorylation
PRKDC	“down-regulates quantity by destabilization”	TOP1	phosphorylation
PRKDC	“up-regulates activity”	YBX1	phosphorylation
PRKDC	“up-regulates activity”	MITF	phosphorylation
PRKDC	“down-regulates quantity by destabilization”	PPARGC1A	phosphorylation
PLK1	“up-regulates activity”	PRKDC	phosphorylation
PRKDC	“down-regulates activity”	ATM	phosphorylation
LYN	“down-regulates activity”	PRKDC	phosphorylation

Protein complexes (CORUM) (15)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

15 complexes by size:

Complex	Subunits	Members
★ CDC5L complex	30	SRRM1, SF3B1, SRSF1, CDC5L, DYNC1H1, GCN1, HSPA8, PPP1CA, SF3B2, SCAF8, SNRPA, SRSF2, BZW1, RBMX, SFPQ, SNRPA1, SNRPD3, TCF4, PLRG1, SNRPD2, TOP2A, ILF2, SF3B4, SNRPD1, SFI1, BCAS2, CWC15, PPM1D, PRKDC, PRPF19
H2A.Z histone-exchange complex p400/TIP60	27	ZNHIT1, ACTL6A, DMAP1, MORF4L1, MRGBP, RUVBL1, VPS72, YEATS4, BRD8, H4C1, ING3, IPO9, PRKDC, SRCAP, ANP32E, EP400, EPC1, EPC2, H2AZ1, H2BC4, H3C1, KAT5, MORF4L2, RUVBL2, TRRAP, XRCC5, XRCC6
★ MegaTrans complex	10	ESR1, FOS, GATA3, STAT1, XRCC5, XRCC6, FOXA1, PRKDC, RARA, TFAP2C
★ MegaTrans complex	10	FOS, FOXA1, STAT1, XRCC5, XRCC6, ESR1, GATA3, PRKDC, RARG, TFAP2C
HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex	9	MATR3, NONO, PRKDC, RBM14, HEXIM1, PSPC1, SFPQ, XRCC5, XRCC6
DNA-PK-Ku-eIF2-NF90-NF45 complex	8	XRCC6, EIF2S1, EIF2S2, EIF2S3, ILF2, ILF3, PRKDC, XRCC5
PAXX complex	8	PRKDC, XRCC4, XRCC5, XRCC6, DCLRE1C, LIG4, NHEJ1, PAXX
★ TRBP-DNA-PK complex	7	PARP1, PRKDC, TOP1, XRCC5, XRCC6, NCOA6, NUMA1
DHX9-ADAR-vigilin-DNA-PK-Ku antigen complex	6	DHX9, HDLBP, PRKDC, XRCC5, XRCC6, ADAR
HDLBP-PRKDC-XRCC5-XRCC6 complex	4	HDLBP, PRKDC, XRCC5, XRCC6
MGC1-DNA-PKcs-Ku complex	4	MDC1, PRKDC, XRCC5, XRCC6
DTNBP1(splice variant 1B)-PRKDC-XRCC5-XRCC6 complex	4	XRCC6, DTNBP1, PRKDC, XRCC5
DTNBP1 (splice variant 1A)-PRKDC-XRCC5-XRCC6 complex	4	DTNBP1, PRKDC, XRCC5, XRCC6
DNA-PK-Ku complex	3	XRCC5, XRCC6, PRKDC
Artemis-DNA-PK complex	2	DCLRE1C, PRKDC

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Response of endothelial cells to shear stress	5	30.7×	2e-04
Cellular responses to mechanical stimuli	5	26.5×	2e-04
Nonhomologous End-Joining (NHEJ)	5	17.1×	8e-04
Signaling by Receptor Tyrosine Kinases	7	7.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	6	37.9×	5e-06
double-strand break repair via nonhomologous end joining	5	36.3×	4e-05
positive regulation of miRNA transcription	5	25.1×	2e-04
telomere maintenance	5	23.1×	2e-04
double-strand break repair	5	17.5×	8e-04
negative regulation of canonical NF-kappaB signal transduction	5	14.8×	1e-03
transcription by RNA polymerase II	9	10.9×	3e-05
positive regulation of canonical NF-kappaB signal transduction	6	7.5×	5e-03

Disease & clinical

Genetic variants

Variant evidence for PRKDC: 4,961 ClinVar records (4 pathogenic / likely pathogenic); 1 CIViC cancer variant; 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

4,961 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	2596
Likely benign	2052
Benign	89

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
154322	NM_006904.7(PRKDC):c.9185T>G (p.Leu3062Arg)	Pathogenic	criteria provided, single submitter	2
4813774	NM_006904.7(PRKDC):c.5589del (p.Phe1863fs)	Likely pathogenic	criteria provided, single submitter	1
154323	NM_006904.7(PRKDC):c.10721C>T (p.Ala3574Val)	Pathogenic	no assertion criteria provided	1
688051	GRCh37/hg19 8q11.21(chr8:48730498-48829786)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PRKDC’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 44 predictions of 6,186):

Position(s)	Effect	Δscore	Sites
8:47774378–47774379	acceptor_loss	1.0000	5
8:47777684–47777685	donor_loss	1.0000	5
8:47777688	donor_gain	1.0000
8:47777875–47777876	acceptor_loss	1.0000	6
8:47779002–47779003	donor_loss	1.0000	5
8:47779007	donor_gain	1.0000
8:47779094–47779095	acceptor_loss	1.0000	6
8:47782160–47782161	donor_loss	1.0000	4
8:47782255–47782256	acceptor_loss	1.0000	6
8:47782376–47782377	donor_loss	1.0000	5

AlphaMissense

6,100 missense substitutions predicted likely pathogenic (of 27,291 scored), across 1,881 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D3941	8	0.990	0.998
D3761	8	0.988	0.995
N3927	8	0.975	0.996
D3757	8	0.973	0.994
D3922	8	0.972	0.994
H3924	8	0.965	0.986
F3946	8	0.951	0.991
D619	8	0.948	0.976
F3942	8	0.944	0.995
F4005	8	0.929	0.986
F369	8	0.920	0.981
F2157	8	0.911	0.973
H1772	8	0.908	0.979
F2606	8	0.904	0.989
D2086	8	0.901	0.971
D2782	8	0.899	0.955
F1990	8	0.885	0.979
H2091	8	0.875	0.961
F1384	8	0.872	0.982
F282	8	0.859	0.977

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

5 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	unfavorable	6.38e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.00012
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000376
Rectum Adenocarcinoma (validation)	favorable	0.000518
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000555

Disease associations

OMIM: gene MIM:600899 | disease phenotypes: MIM:615966

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
severe combined immunodeficiency due to DNA-PKcs deficiency	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
severe combined immunodeficiency due to DNA-PKcs deficiency	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (1): severe combined immunodeficiency due to DNA-PKcs deficiency (MONDO:0014423)

Orphanet (1): Severe combined immunodeficiency due to DNA-PKcs deficiency (Orphanet:317425)

HPO phenotypes

28 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000331	Short chin
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0001250	Seizure
HP:0001302	Pachygyria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0002079	Hypoplasia of the corpus callosum
HP:0002783	Recurrent lower respiratory tract infections
HP:0003429	CNS hypomyelination
HP:0003593	Infantile onset
HP:0004430	Severe combined immunodeficiency
HP:0005403	Decreased total T cell count
HP:0009879	Simplified gyral pattern
HP:0010557	Overlapping fingers
HP:0010976	Decreased total B cell count
HP:0011107	Recurrent aphthous stomatitis
HP:0011220	Prominent forehead
HP:0012176	Abnormal natural killer cell morphology
HP:0012444	Brain atrophy

GWAS associations

4 associations:

Study	Trait	p-value
GCST90002390_532	Mean corpuscular hemoglobin	2e-10
GCST90002384_19	Hemoglobin	5e-10
GCST012490_137	Femur bone mineral density x serum urate levels interaction	2e-8
GCST010988_540	Adult body size	5e-8

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3142 (SINGLE PROTEIN), CHEMBL4106136 (PROTEIN COMPLEX)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the PRKDC protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
CC-115	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 113,635 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

23 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2216870	IDELALISIB	4	10,756
CHEMBL3643413	LENIOLISIB	4	379
CHEMBL422	TRIFLUOPERAZINE	4	20,190
CHEMBL2017974	BUPARLISIB	3	6,850
CHEMBL4285417	CERALASERTIB	3	1,563
CHEMBL1879463	DACTOLISIB	3	8,349
CHEMBL265502	SURAMIN	3	37,133
CHEMBL3586573	CC-115	2	1,300
CHEMBL1922094	APITOLISIB	2	3,224
CHEMBL2165191	AZD-6482	2	974
CHEMBL3989870	BERZOSERTIB	2	1,341
CHEMBL4084907	BIMIRALISIB	2	1,722
CHEMBL3984425	EGANELISIB	2	1,267
CHEMBL3622533	FIMEPINOSTAT	2	2,628
CHEMBL1236962	OMIPALISIB	2	4,170
CHEMBL3120215	OSI-027	2	1,950
CHEMBL521851	PICTILISIB	2	6,322
CHEMBL3360203	PILARALISIB	2	2,838
CHEMBL4439259	AZD-7648	1	342
CHEMBL3747513	CB-5083	1	337
CHEMBL4647810	ELIMUSERTIB	1
CHEMBL4297629	NEDISERTIB	1
CHEMBL3112866	SAR-260301	1

Clinical evidence (CIViC)

Drug × variant × indication, from 2 curated evidence items; also 1 oncogenic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

2 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
PRKDC Mutation	Anti-PD1 Monoclonal Antibody + Anti-CTLA-4 Monoclonal Antibody	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID13225
PRKDC Mutation	Anti-CTLA-4 Monoclonal Antibody	Melanoma	Sensitivity/Response	CIViC B	EID13226

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

Mutation.

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Other PIKK family kinases

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
torin 2	Inhibition	9.3	pIC50
XRD-0394	Inhibition	9.2	pIC50
PIK-75	Inhibition	8.7	pIC50
compound 82 [PMID: 21332118]	Inhibition	8.52	pKi
peposertib	Inhibition	8.52	pIC50
KU-0060648	Inhibition	8.3	pIC50
NU-7441	Inhibition	7.85	pIC50
PI-103	Inhibition	7.64	pIC50
PP121	Inhibition	7.22	pIC50
BAY-8400	Inhibition	7.09	pIC50
AZD7648	Inhibition	7.04	pIC50
DNA-PK inhibitor III	Inhibition	6.92	pIC50
wortmannin	Inhibition	6.92	pKi
NU-7026	Inhibition	6.64	pIC50
DNA-PK inhibitor V	Inhibition	6.57	pIC50
lartesertib	Inhibition	6.22	pIC50

Binding affinities (BindingDB)

1534 measured of 2247 human assays (2261 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
9-(3-Hydroxyadamantan-1-yl)-7-methyl-2-((7-methylquinolin-6-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
Ethyl-3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-[3-(hydroxymethyl)adamantan-1-yl]-8,9-dihydro-7H-purin-8-one	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
4-((9-3-Hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-3-methylbenzonitrile	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
4-((9-(3-Hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-3-methylbenzamide	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
2-fluoro-4-[[9-(4-hydroxy-1-adamantyl)-7-methyl-8-oxopurin-2-yl]amino]-5-methylbenzamide	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
5-[7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxopurin-9-yl]adamantane-2-carbonitrile	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
2-Fluoro-4-((9-(3-hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-5-methylbenzamide	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
2-Fluoro-5-methyl-4-((7-methyl-8-oxo-9-(4-oxoadamantan-1-yl)-8,9-dihydro-7H-purin-2-yl)amino)benzamide	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
4-((9-(4,4-Dimethoxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide	IC50	0.01 nM	US-12552793: Purine derivative and medical use thereof
7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one	IC50	0.03 nM	US-12552793: Purine derivative and medical use thereof
9-(4-deuterio-4-hydroxy-1-adamantyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	IC50	0.03 nM	US-12552793: Purine derivative and medical use thereof
9-(4-Hydroxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.06 nM	US-12552793: Purine derivative and medical use thereof
9-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.07 nM	US-20250263753: BRIDGED CYCLE-BASED INHIBITORS OF DNA-DEPENDENT PROTEIN KINASE AND COMPOSITIONS AND APPLICATION IN GENE EDITING
3-(7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carbonitrile	IC50	0.08 nM	US-12552793: Purine derivative and medical use thereof
7-Methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one	IC50	0.08 nM	US-12552793: Purine derivative and medical use thereof
CHEMBL5566630	IC50	0.1 nM
CHEMBL5563688	IC50	0.1 nM
9-(3-Methoxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.1 nM	US-12552793: Purine derivative and medical use thereof
5-[7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxopurin-9-yl]adamantane-2-carbonitrile	IC50	0.1 nM	US-12552793: Purine derivative and medical use thereof
4-[7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxopurin-9-yl]adamantane-1-carbonitrile	IC50	0.1 nM	US-12552793: Purine derivative and medical use thereof
9-(4,4-Dimethoxyadamantan-1-yl)-7-methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.1 nM	US-12552793: Purine derivative and medical use thereof
CHEMBL5570653	IC50	0.11 nM
CHEMBL5180090	IC50	0.12 nM
CHEMBL5194436	IC50	0.13 nM
9-(4-hydroxy-1-adamantyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-4,5-dihydropurin-8-one	IC50	0.13 nM	US-12552793: Purine derivative and medical use thereof
CHEMBL4450232	IC50	0.2 nM
3-[3-[4-[dideuterio(methylamino)methyl]phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine	IC50	0.2 nM
CHEMBL5591635	IC50	0.2 nM
CHEMBL4553941	IC50	0.251 nM
2-[[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxymethyl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[8-[difluoro(phenyl)methoxy]-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
methyl 2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)acetate	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl] 4-methylbenzenesulfonate	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-phenylphosphinic acid	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[7-methoxy-3-methyl-8-[[3-(morpholin-4-ylmethyl)phenyl]methoxy]pyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[7-methoxy-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)pyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[8-[[3-(aminomethyl)phenyl]methoxy]-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxymethyl]pyridine-2-carbonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[8-[[3-(dimethylamino)phenyl]methoxy]-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[7-methoxy-3-methyl-8-[[3-(2-methyl-1,3-thiazol-4-yl)phenyl]methoxy]pyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-N-[2-(4-ethylpiperazin-1-yl)ethyl]-2-(4-fluorophenyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-N-[2-(dimethylamino)ethyl]-2-(4-fluorophenyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
N-(cyanomethoxy)-2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)-N-(2-sulfamoylethyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(3-ethyl-7,8-dimethoxypyrazolo[3,4-c]quinolin-1-yl)-3-fluorobenzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(7,8-dimethoxy-3-propylpyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(7,8-dimethoxy-3-propan-2-ylpyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(3-cyclopropyl-7,8-dimethoxypyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(7,8-dimethoxy-3-prop-2-enylpyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines

ChEMBL bioactivities

2090 potent at pChembl≥5 of 2153 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.07943	nM	CHEMBL4447991
10.00	IC50	0.1	nM	CHEMBL5566630
10.00	IC50	0.1	nM	CHEMBL5563688
9.96	IC50	0.11	nM	CHEMBL5570653
9.92	IC50	0.12	nM	CHEMBL5180090
9.89	IC50	0.13	nM	CHEMBL5194436
9.80	IC50	0.1585	nM	CHEMBL4560221
9.80	IC50	0.158	nM	CHEMBL6065576
9.80	IC50	0.158	nM	CHEMBL5890243
9.80	IC50	0.158	nM	CHEMBL4560221
9.70	IC50	0.1995	nM	CHEMBL4450232
9.70	IC50	0.2	nM	CHEMBL5591635
9.70	IC50	0.2	nM	CHEMBL5889927
9.60	IC50	0.2512	nM	CHEMBL4553941
9.60	IC50	0.251	nM	CHEMBL5980589
9.55	IC50	0.28	nM	OMIPALISIB
9.52	IC50	0.3	nM	CHEMBL3646708
9.52	IC50	0.3	nM	CHEMBL3646711
9.52	IC50	0.3	nM	CHEMBL3646712
9.52	IC50	0.3	nM	CHEMBL3646718
9.52	IC50	0.3	nM	CHEMBL3646719
9.52	IC50	0.3	nM	CHEMBL3646722
9.52	IC50	0.3	nM	CHEMBL3646724
9.52	IC50	0.3	nM	CHEMBL3646726
9.52	IC50	0.3	nM	CHEMBL3646732
9.52	IC50	0.3	nM	CHEMBL3646735
9.52	IC50	0.3	nM	CHEMBL3639456
9.52	IC50	0.3	nM	CHEMBL3646741
9.52	IC50	0.3	nM	CHEMBL3646742
9.52	IC50	0.3	nM	CHEMBL3646744
9.52	IC50	0.3	nM	CHEMBL3646745
9.52	IC50	0.3	nM	CHEMBL3646750
9.52	IC50	0.3	nM	CHEMBL3646752
9.52	IC50	0.3	nM	CHEMBL3646753
9.52	IC50	0.3	nM	CHEMBL3646755
9.52	IC50	0.3	nM	CHEMBL3646756
9.52	IC50	0.3	nM	CHEMBL3646758
9.52	IC50	0.3	nM	CHEMBL3646760
9.52	IC50	0.3	nM	CHEMBL3646761
9.52	IC50	0.3	nM	CHEMBL3646768
9.52	IC50	0.3	nM	CHEMBL3667683
9.52	IC50	0.3	nM	CHEMBL3667686
9.52	IC50	0.3	nM	CHEMBL3672673
9.52	IC50	0.3	nM	CHEMBL3672679
9.52	IC50	0.3	nM	CHEMBL3672681
9.52	IC50	0.3	nM	CHEMBL3672683
9.52	IC50	0.3	nM	CHEMBL3672684
9.50	IC50	0.3162	nM	CHEMBL4555040
9.50	IC50	0.3162	nM	CHEMBL4581254
9.50	IC50	0.316	nM	CHEMBL4581254

PubChem BioAssay actives

1135 with measured affinity, of 2131 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
9-(4-hydroxycyclohexyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylquinolin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylquinoxalin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylcinnolin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylquinazolin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0001	uM
7-methyl-2-[(4-methyl-6-thiophen-2-yl-3-pyridinyl)amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0001	uM
N-(6-methylquinolin-7-yl)-5-(oxan-4-yl)-4H-[1,2,4]triazolo[4,3-f]pteridin-7-amine	2104207: Inhibition of human full-length DNA-PK using EPPLSQEAFADLWKK as substrate incubated for 60 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0001	uM
9-cyclohexyl-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0002	uM
9-(4,4-difluorocyclohexyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0002	uM
5-[4-methyl-5-[[7-methyl-9-(oxan-4-yl)-8-oxopurin-2-yl]amino]-2-pyridinyl]furan-2-carbaldehyde	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0002	uM
9-(4-hydroxy-4-methylcyclohexyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0003	uM
9-(4-hydroxycyclohexyl)-2-(4-methoxy-2-methylanilino)-7-methylpurin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0003	uM
9-(4-hydroxycyclohexyl)-7-methyl-2-[(7-methylimidazo[1,2-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0003	uM
N-(6-methylquinolin-7-yl)-5-(oxan-4-yl)-6H-imidazo[1,2-f]pteridin-3-amine	2104207: Inhibition of human full-length DNA-PK using EPPLSQEAFADLWKK as substrate incubated for 60 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0003	uM
2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)-3-pyridinyl]benzenesulfonamide	2154071: Inhibition of DNA-PK (unknown origin)	ic50	0.0003	uM
7-methyl-2-[(7-methylimidazo[1,2-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0004	uM
7-methyl-2-[(7-methylquinolin-6-yl)amino]-9-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0004	uM
7-methyl-2-[2-methyl-4-(1H-1,2,4-triazol-5-yl)anilino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0004	uM
7-methyl-2-[[4-methyl-6-(1H-pyrazol-4-yl)-3-pyridinyl]amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0004	uM
2-[[6-[1-(difluoromethyl)pyrazol-4-yl]-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0004	uM
(S)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol	2066816: Inhibition of human DNA-PK using EPPLSQEAFADLWK as substrate in presence of ATP by kinase hotspot assay	ic50	0.0004	uM
6-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-3H-quinazolin-4-one	507077: Inhibition of DNA-PK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0005	uM
9-[(3R,4R)-4-fluoropyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0005	uM
9-(6-amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2-one	591849: Inhibition of DNA-PK	ic50	0.0005	uM
8-dibenzothiophen-4-yl-2-morpholin-4-ylchromen-4-one	257403: Inhibitory activity against DNA-dependent protein kinase receptor	ki	0.0006	uM
7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0006	uM
9-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0006	uM
1-methyl-N-(6-methylquinolin-7-yl)-5-(oxan-4-yl)-4H-[1,2,4]triazolo[4,3-f]pteridin-7-amine	2104207: Inhibition of human full-length DNA-PK using EPPLSQEAFADLWKK as substrate incubated for 60 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0006	uM
7-methyl-9-(1-methylpiperidin-4-yl)-2-[(7-methylquinoxalin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0007	uM
7-methyl-2-[(7-methylquinolin-6-yl)amino]-9-piperidin-4-ylpurin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0007	uM
2-[[6-(furan-2-yl)-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0007	uM
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile	2066816: Inhibition of human DNA-PK using EPPLSQEAFADLWK as substrate in presence of ATP by kinase hotspot assay	ic50	0.0008	uM
5-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-(oxan-4-yl)-7H-pteridin-6-one	1867755: Inhibition of human native full length DNA-PK by ADP-Glo assay	ic50	0.0008	uM
7-methyl-2-[(4-methyl-6-thiophen-3-yl-3-pyridinyl)amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0008	uM
2-[[6-(furan-3-yl)-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0008	uM
9-[(3S)-1-(2-hydroxyethyl)pyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0008	uM
N-[5-(7’-fluoro-3’-methyl-2’-oxospiro[cyclobutane-1,1’-pyrrolo[2,3-c]quinoline]-8’-yl)-2-[2-(propan-2-ylamino)ethoxy]-3-pyridinyl]methanesulfonamide	2066601: Inhibition of DNA-PK in human HCT-116 cells measured after 1 hr by Bradford assay	ic50	0.0009	uM
7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]-9-piperidin-4-ylpurin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0009	uM
N-[2-[3-(dimethylamino)propoxy]-5-(3’-methyl-2’-oxospiro[cyclobutane-1,1’-pyrrolo[2,3-c]quinoline]-8’-yl)-3-pyridinyl]-1,1,1-trifluoromethanesulfonamide	1872253: Inhibition of full-length human DNA-PK expressed in baculovirus expression system using p53 as substrate incubated for 1 hr in presence of ATP by ELISA	ic50	0.0010	uM
N-[2-[3-(dimethylamino)propoxy]-5-(3’-methyl-2’-oxospiro[cyclobutane-1,1’-pyrrolo[2,3-c]quinoline]-8’-yl)-3-pyridinyl]-2-ethyl-1,3-thiazole-5-sulfonamide	1872253: Inhibition of full-length human DNA-PK expressed in baculovirus expression system using p53 as substrate incubated for 1 hr in presence of ATP by ELISA	ic50	0.0010	uM
7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)purin-8-one	1872240: Inhibition of human DNA-PK using p53 as substrate incubated for 30 mins in presence of by HTRF assay	ic50	0.0010	uM
1,1,5’-trimethyl-2’-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]spiro[cyclohexane-4,7’-pyrrolo[3,2-d]pyrimidine]-6’-one	1872240: Inhibition of human DNA-PK using p53 as substrate incubated for 30 mins in presence of by HTRF assay	ic50	0.0010	uM
2-(5-acetyl-2,3-dihydroindol-1-yl)-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
2-[[6-(3,4-dimethoxyphenyl)-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
7-methyl-2-[[5-methyl-2-(1-methylpyrazol-4-yl)-4-pyridinyl]amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
9-[(3R,5S)-3,5-dimethyl-1-adamantyl]-7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
9-(1-acetylpiperidin-4-yl)-7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]-9-(1-methylsulfonylpiperidin-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
7-methyl-9-[(3S)-1-methylpyrrolidin-3-yl]-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0014	uM

CTD chemical–gene interactions

129 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases expression, affects binding, decreases reaction, decreases phosphorylation (+3 more)	5
Benzo(a)pyrene	decreases methylation, affects methylation, decreases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression	5
Arsenic	decreases expression, increases expression, decreases reaction, increases response to substance, affects cotreatment (+1 more)	4
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Cisplatin	increases expression, affects cotreatment, increases response to substance, decreases response to substance	3
Doxorubicin	decreases expression, decreases reaction, affects reaction, increases activity, increases phosphorylation (+1 more)	3
arsenite	decreases stability, increases degradation, affects binding, decreases reaction, increases activity (+2 more)	2
cobaltous chloride	decreases expression	2
2-(morpholin-4-yl)benzo(h)chromen-4-one	decreases activity, decreases phosphorylation, increases reaction	2
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, affects response to substance, decreases expression	2
IC486241	increases reaction, decreases reaction, increases phosphorylation	2
Bortezomib	affects reaction, increases activity, decreases reaction, increases cleavage, decreases expression	2
Irinotecan	decreases reaction, increases phosphorylation	2
Benzene	affects expression, increases expression	2
Caffeine	affects phosphorylation, increases activity, increases phosphorylation, increases reaction	2
Curcumin	decreases expression, decreases reaction	2
Fluorouracil	affects cotreatment, increases response to substance, affects reaction, decreases expression	2
Nickel	increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Phenol	affects localization, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
lasiocarpine	increases expression	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1

ChEMBL screening assays

363 unique, capped per target: 363 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1054863	Binding	Inhibition of DNA-PK at 10 uM by HotSpot assay relative to control	Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

13 cell lines: 12 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0400	M059J	Cancer cell line	Male
CVCL_1R01	HCT116-DNAPKcs(+/-)	Cancer cell line	Male
CVCL_B9QF	Abcam A-549 PRKDC KO	Cancer cell line	Male
CVCL_D9PU	Ubigene HEK293 PRKDC KO	Transformed cell line	Female
CVCL_DX08	HAP1 PRKDC (-) PAXX (-)	Cancer cell line	Male
CVCL_DX10	HAP1 PRKDC (-) XRCC4 (-)	Cancer cell line	Male
CVCL_F1MC	HyCyte A-549 KO-hPRKDC	Cancer cell line	Male
CVCL_HD89	HCT 116 PRKDC(+/-)	Cancer cell line	Male
CVCL_HD90	HCT 116 PRKDC(-/-)	Cancer cell line	Male
CVCL_HE07	NALM-6 PRKDC(+/-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00014638	Phase 4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	Phase 4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	Phase 4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	Phase 4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	Phase 4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	Phase 4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	Phase 4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	Phase 4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	Phase 4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	Phase 4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	Phase 4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	Phase 4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	Phase 4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	Phase 4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	Phase 4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	Phase 4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	Phase 4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	Phase 4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	Phase 4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	Phase 4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	Phase 4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	Phase 4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	Phase 4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	Phase 4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	Phase 4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	Phase 4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	Phase 4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	Phase 4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	Phase 4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	Phase 4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	Phase 4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	Phase 4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	Phase 4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	Phase 4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	Phase 4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	Phase 4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	Phase 4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	Phase 4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	Phase 4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	Phase 4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer
NCT00756717	Phase 4	COMPLETED	Study Of MK-0752 In Combination With Tamoxifen Or Letrozole to Treat Early Stage Breast Cancer
NCT00766532	Phase 4	COMPLETED	Do Aromatase Inhibitors (AIs) Decrease Intestinal Calcium Absorption?
NCT00768222	Phase 4	COMPLETED	Coated VICRYL* Plus Suture Compared to Chinese Silk in Scheduled Breast Cancer Surgery
NCT00772824	Phase 4	COMPLETED	Study of the Effect of Glutamine Supplementation on Chemotherapy Induced Toxicities in Breast Cancer Patients
NCT00774241	Phase 4	WITHDRAWN	PRIMADOS Study:A Study of Avastin (Bevacizumab) Plus Docetaxel for First Line Treatment of Patients With Metastatic Breast Cancer
NCT00812864	Phase 4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00872859	Phase 4	COMPLETED	The BREASTrial:Breast Reconstruction Evaluation Using Acellular Dermal Matrix as a Sling Trial
NCT00882089	Phase 4	COMPLETED	Use of the Contura™ Catheter in Intermediate-Risk, Pathological Stage 0, I, or II (Up to 3.0 cm) Breast Cancer Patients
NCT00882596	Phase 4	COMPLETED	Use of the Contura™ Catheter to Deliver Accelerated Partial Breast Irradiation to Low-risk Breast Cancer Patients
NCT00904410	Phase 4	COMPLETED	Early Assessment of the Response to Neo-adjuvant Chemotherapy in Breast Cancer Patients With FDG-PET
NCT00912639	Phase 4	UNKNOWN	A Clinical Trial of Paclitaxel Loaded Polymeric Micelle in Patients With Taxane-Pretreated Recurrent Breast Cancer
NCT00912938	Phase 4	UNKNOWN	Evaluate the Relationship of Bone Remodeling Markers for Skeletal Complications in Metastatic Breast Cancer Patients
NCT01035099	Phase 4	COMPLETED	RCT of Fixed vs Titrated Letrozole in Breast Cancer Patient Undergoing IVF
NCT01049295	Phase 4	UNKNOWN	Omega-3 Fatty Acids and Chemotherapy-induced Neuropathy and Inflammation in Breast Cancer
NCT01072318	Phase 4	UNKNOWN	Extended Adjuvant Treatment With Letrozole in Breast Cancer Who Complete 5 Years of Toremifene
NCT01094184	Phase 4	COMPLETED	A Study of Bevacizumab With Taxane Therapy in Participants With Triple Negative Breast Cancer
NCT01156961	Phase 4	WITHDRAWN	A Study of The Safety Profile of First-line Avastin (Bevacizumab) in Combination With Paclitaxel in Patients With Locally Recurrent or Metastatic Her2-negative Breast Cancer (AVATAX)
NCT01199432	Phase 4	COMPLETED	Comparative Efficiency of Three Regimen, CEFci, CEF and EC as Neoadjuvant Chemotherapy for Primary Breast Cancer
NCT01216254	Phase 4	UNKNOWN	Clinical Trial Comparing Outcomes of Breast Conserving Operations With Classic v High-frequency Electrocoagulation
NCT01231204	Phase 4	COMPLETED	Prevention of Post-Mastectomy Breast Pain Using Ambulatory Continuous Paravertebral Blocks

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PRKDC across ~30M SureChEMBL compounds — explore on Sugi Predict.