POLE3

Summary

POLE3 (DNA polymerase epsilon 3, accessory subunit, HGNC:13546) is a protein-coding gene on chromosome 9q32, encoding DNA polymerase epsilon subunit 3 (Q9NRF9). Accessory component of the DNA polymerase epsilon complex. It is a selective cancer dependency (DepMap: 28.8% of cell lines).

POLE3 is a histone-fold protein that interacts with other histone-fold proteins to bind DNA in a sequence-independent manner. These histone-fold protein dimers combine within larger enzymatic complexes for DNA transcription, replication, and packaging.

Source: NCBI Gene 54107 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 6 total
• GTEx eGene: eQTL in 35 tissues, sQTL in 0 (q < 0.05)
• Cancer dependency (DepMap): dependent in 28.8% of screened cell lines
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 1.15 (unconstrained)
• MANE Select transcript: NM_017443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13546
Approved symbol	POLE3
Name	DNA polymerase epsilon 3, accessory subunit
Location	9q32
Locus type	gene with protein product
Status	Approved
Aliases	CHRAC17, Ybl1, p17, CHARAC17, CHRAC2
Ensembl gene	ENSG00000148229
Ensembl biotype	protein_coding
OMIM	607267
Entrez	54107

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000374171

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

ENST00000374171, ENST00000374169, ENST00000475080, ENST00000479871, ENST00000858453, ENST00000940582, ENST00001056332, ENST00001135612

RefSeq mRNA: 3 — MANE Select: NM_017443 NM_001278255, NM_001433719, NM_017443

CCDS: CCDS6795

Canonical transcript exons

ENST00000374171 — 5 exons

Exon	Start	End
ENSE00000983926	113410055	113410140
ENSE00001327295	113410617	113410675
ENSE00001462692	113410228	113410408
ENSE00003533563	113407235	113408983
ENSE00003598088	113409610	113409728

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.6133 / max 443.1959, expressed in 1822 samples.

Highest expression (Bgee): primordial germ cell in gonad, gastrocnemius, muscle of leg, granulocyte, monocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLE3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 35 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 35 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	3.4e-30	-0.54	9:113419619:G:GAGTTATA
Thyroid	eqtl	7.0e-30	-0.65	9:113417085:G:A
Adipose Visceral Omentum	eqtl	4.4e-26	-0.58	9:113448483:C:G
Adipose Subcutaneous	eqtl	9.1e-17	-0.48	9:113448314:C:T
Artery Aorta	eqtl	5.7e-16	-0.49	9:113406788:G:A
Lung	eqtl	8.8e-16	-0.37	9:113571599:G:A
Artery Tibial	eqtl	9.3e-16	-0.42	9:113407452:TA:T
Esophagus Muscularis	eqtl	1.0e-15	-0.31	9:113448483:C:G
Esophagus Mucosa	eqtl	2.5e-15	-0.28	9:113406788:G:A
Cells Cultured fibroblasts	eqtl	9.7e-15	-0.23	9:113405962:G:C
Stomach	eqtl	3.1e-14	-0.44	9:113590093:C:T
Heart Atrial Appendage	eqtl	3.9e-14	-0.52	9:113406788:G:A
Esophagus Gastroesophageal Junction	eqtl	2.2e-13	-0.35	9:113446041:C:T
Colon Transverse	eqtl	3.4e-13	-0.43	9:113456060:T:G
Minor Salivary Gland	eqtl	2.0e-09	-0.65	9:113405962:G:C
Skin Sun Exposed Lower leg	eqtl	4.1e-09	-0.26	9:113406788:G:A
Muscle Skeletal	eqtl	1.2e-08	-0.32	9:113584500:TGAG:T
Pancreas	eqtl	1.7e-08	-0.46	9:113584500:TGAG:T
Spleen	eqtl	3.5e-08	-0.44	9:113405962:G:C
Breast Mammary Tissue	eqtl	4.4e-08	-0.38	9:113448483:C:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
102106	40.6971	1821
102105	1.8255	1065
102108	0.9030	487
102104	0.8069	456
102107	0.3809	161

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.95	gold quality
gastrocnemius	UBERON:0001388	94.45	gold quality
muscle of leg	UBERON:0001383	94.24	gold quality
granulocyte	CL:0000094	94.06	gold quality
monocyte	CL:0000576	93.93	gold quality
leukocyte	CL:0000738	93.85	gold quality
mononuclear cell	CL:0000842	93.80	gold quality
penis	UBERON:0000989	93.75	gold quality
ganglionic eminence	UBERON:0004023	93.73	gold quality
endometrium epithelium	UBERON:0004811	93.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.72	gold quality
rectum	UBERON:0001052	92.59	gold quality
ventricular zone	UBERON:0003053	92.56	gold quality
bone marrow	UBERON:0002371	92.52	gold quality
cerebellar hemisphere	UBERON:0002245	92.49	gold quality
cerebellar cortex	UBERON:0002129	92.47	gold quality
muscle organ	UBERON:0001630	92.36	gold quality
esophagus mucosa	UBERON:0002469	92.33	gold quality
right adrenal gland	UBERON:0001233	92.27	gold quality
right adrenal gland cortex	UBERON:0035827	92.18	gold quality
skin of leg	UBERON:0001511	92.16	gold quality
skin of abdomen	UBERON:0001416	92.14	gold quality
left adrenal gland	UBERON:0001234	92.00	gold quality
lymph node	UBERON:0000029	91.77	gold quality
tibial artery	UBERON:0007610	91.65	gold quality
popliteal artery	UBERON:0002250	91.64	gold quality
cortical plate	UBERON:0005343	91.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.48	gold quality
left adrenal gland cortex	UBERON:0035825	91.47	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.44	gold quality
esophagus	UBERON:0001043	91.37	gold quality
cerebellum	UBERON:0002037	91.27	gold quality
zone of skin	UBERON:0000014	91.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.24	gold quality
adrenal gland	UBERON:0002369	91.23	gold quality
right testis	UBERON:0004534	91.20	gold quality
paraflocculus	UBERON:0005351	91.13	gold quality
descending thoracic aorta	UBERON:0002345	91.00	gold quality
body of pancreas	UBERON:0001150	90.97	gold quality
islet of Langerhans	UBERON:0000006	90.88	gold quality
spleen	UBERON:0002106	90.71	gold quality
aorta	UBERON:0000947	90.70	gold quality
adrenal cortex	UBERON:0001235	90.66	gold quality
left testis	UBERON:0004533	90.54	gold quality
adrenal tissue	UBERON:0018303	90.51	gold quality
mucosa of transverse colon	UBERON:0004991	90.48	gold quality
testis	UBERON:0000473	90.43	gold quality
right coronary artery	UBERON:0001625	90.42	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.42	gold quality
epithelium of nasopharynx	UBERON:0001951	90.39	gold quality
vermiform appendix	UBERON:0001154	90.36	gold quality
left coronary artery	UBERON:0001626	90.36	gold quality
left uterine tube	UBERON:0001303	90.31	gold quality
lower esophagus	UBERON:0013473	90.30	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.30	gold quality
epithelium of esophagus	UBERON:0001976	90.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.24	gold quality
pancreas	UBERON:0001264	90.21	gold quality
embryo	UBERON:0000922	90.15	gold quality
bone marrow cell	CL:0002092	90.14	gold quality
transverse colon	UBERON:0001157	89.97	gold quality
esophagus squamous epithelium	UBERON:0006920	89.90	gold quality
prefrontal cortex	UBERON:0000451	89.83	gold quality
sural nerve	UBERON:0015488	89.65	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.61	gold quality
mucosa of stomach	UBERON:0001199	89.59	gold quality
thoracic aorta	UBERON:0001515	89.59	gold quality
body of stomach	UBERON:0001161	89.58	gold quality
stromal cell of endometrium	CL:0002255	89.50	gold quality
coronary artery	UBERON:0001621	89.47	gold quality
ascending aorta	UBERON:0001496	89.44	gold quality
upper lobe of left lung	UBERON:0008952	89.31	gold quality
minor salivary gland	UBERON:0001830	89.28	gold quality
caecum	UBERON:0001153	89.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.25	gold quality
ectocervix	UBERON:0012249	89.10	gold quality
secondary oocyte	CL:0000655	89.06	gold quality
calcaneal tendon	UBERON:0003701	89.01	gold quality
upper lobe of lung	UBERON:0008948	89.01	gold quality
sigmoid colon	UBERON:0001159	89.00	gold quality
upper leg skin	UBERON:0004262	89.00	gold quality
heart left ventricle	UBERON:0002084	88.96	gold quality
tonsil	UBERON:0002372	88.87	gold quality
omental fat pad	UBERON:0010414	88.87	gold quality
palpebral conjunctiva	UBERON:0001812	88.86	gold quality
peritoneum	UBERON:0002358	88.85	gold quality
mouth mucosa	UBERON:0003729	88.84	gold quality
body of uterus	UBERON:0009853	88.81	gold quality
right lung	UBERON:0002167	88.80	gold quality
colon	UBERON:0001155	88.77	gold quality
large intestine	UBERON:0000059	88.68	gold quality
intestine	UBERON:0000160	88.66	gold quality
cardiac ventricle	UBERON:0002082	88.62	gold quality
small intestine	UBERON:0002108	88.60	gold quality
right frontal lobe	UBERON:0002810	88.58	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.46	gold quality
endocervix	UBERON:0000458	88.45	gold quality
saliva-secreting gland	UBERON:0001044	88.43	gold quality
right uterine tube	UBERON:0001302	88.29	gold quality
adult organism	UBERON:0007023	88.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
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)
Corpus callosum	tissue	110.4
Pons	tissue	107.6
Spinal cord	tissue	107.1
Bone marrow	tissue	107.0	medium
Midbrain	tissue	106.0
Thalamus	tissue	102.8
Medulla oblongata	tissue	101.5
Substantia nigra	tissue	100.6
Superior colliculi	tissue	95.4
Hypothalamus	tissue	90.9
Putamen	tissue	90.5
Cerebellum	tissue	88.5	medium
Cerebral cortex	tissue	86.9	medium
Occipital cortex	tissue	86.9
Septum	tissue	86.7
Periaqueductal gray	tissue	83.9
Hippocampal formation	tissue	83.3
Prefrontal cortex	tissue	82.0
Ventral forebrain	tissue	80.1
Somatosensory cortex	tissue	78.6
Motor cortex	tissue	76.1
Entorhinal cortex	tissue	74.4
Skeletal muscle	tissue	74.1	not detected
Basal ganglia	tissue	72.8	medium
Retrosplenial cortex	tissue	71.5
Olfactory bulb	tissue	69.3
Temporal cortex	tissue	68.7
Retrosplenial and cingulate cortex	tissue	68.6
Amygdala	tissue	64.2
Insular cortex	tissue	58.5
Tonsil	tissue	53.1	medium
Tongue	tissue	52.6
Thymus	tissue	51.3
Lymph node	tissue	50.1	medium
Testis	tissue	38.4	medium
Liver	tissue	35.6	not detected
Skin 1	tissue	34.6	medium
Appendix	tissue	32.9	medium
Esophagus	tissue	31.1	medium
Rectum	tissue	30.8	low
Breast	tissue	29.7	medium
Caudate putamen	tissue	29.3
Spleen	tissue	29.2	not detected
Colon	tissue	27.7	medium
Ovary	tissue	27.1	not detected
Adrenal gland	tissue	27.1	low
Urinary bladder	tissue	26.6	medium
Fallopian tube	tissue	26.6	low
Smooth muscle	tissue	25.9	medium
Salivary gland	tissue	25.7	not detected
Parathyroid gland	tissue	25.1	not detected
Placenta	tissue	25.0	medium
Heart muscle	tissue	24.7	not detected
Epididymis	tissue	24.6	not detected
Frontal cortex	tissue	24.4
Cervix	tissue	24.2	medium
Postcentral gyrus	tissue	24.1
Duodenum	tissue	23.8	medium
Adipose tissue	tissue	23.6	medium
Vagina	tissue	23.5	medium

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — White matter (110.4), Ventral spinal cord (107.1), Dorsal spinal cord (105.3), Dorsal hippocampus (83.3), Ventral hippocampus (76.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, MYC

miRNA regulators (miRDB)

Targeting POLE3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 69 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4261	99.59	70.30	3415

Functional genomics

gnomAD constraint: pLI 0.0128, LOEUF 1.15, missense Z 0.297 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000374171 — one region, missense o/e 0.91. DepMap (CRISPR cell-line fitness): dependent in 28.8% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): LPS6 (-2.353), HCC2450 (-2.287), UWB1.289 (-2.276), KE-37 (-1.992), SNU-1077 (-1.88), KMRC-20 (-1.806), NCI-H446 (-1.784), KP-N-YN (-1.769), 786-O (-1.726), Onda 8 (-1.699), P31/FUJ (-1.672), LPS853 (-1.645), TUHR4TKB (-1.628), WM88 (-1.611), SNU-719 (-1.588).

Literature-anchored findings (GeneRIF, showing 3)

• We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain (PMID:29618620)
• iochemical analyses establish that POLE3-POLE4 is a histone chaperone that promotes tetrasome formation and DNA supercoiling in vitro. In cells, POLE3-POLE4 binds both newly synthesized and parental histones, and its depletion hinders helicase unwinding and chromatin PCNA unloading and compromises coordinated parental histone retention and new histone deposition (PMID:30217558)
• Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors. (PMID:38753485)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pole3	ENSMUSG00000028394
rattus_norvegicus	Pole3	ENSRNOG00000004843
rattus_norvegicus	Pole3	ENSRNOG00000070688

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1933378) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 24 distinct phenotype terms.

Mouse phenotype (MP)	Records
delayed bone ossification	1
short tail	1
small spleen	1
small thymus	1
decreased thymocyte number	1
abnormal brain development	1
abnormal cell cycle	1
decreased fetal size	1
vertebral fusion	1
decreased lymphocyte cell number	1
decreased B cell number	1
decreased double-positive T cell number	1
decreased pre-B cell number	1
decreased immature B cell number	1
decreased gamma-delta T cell number	1
decreased splenocyte number	1
increased thymocyte apoptosis	1
increased grip strength	1
increased DN3 thymocyte number	1
decreased DN4 thymocyte number	1
lethality throughout fetal growth and development, complete penetrance	1
preweaning lethality, complete penetrance	1
preweaning lethality, incomplete penetrance	1
abnormal thymus apoptosis	1

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
Bos taurus	Q3SZN5	100.0%	Diamond
Pongo abelii	Q5R4W3	100.0%	Diamond
Equus caballus	Q6RG77	98.6%	Diamond
Gallus gallus	P25207	97.6%	Diamond
Xenopus laevis	P25211	95.1%	Diamond
Zea mays	P25209	92.7%	Diamond
Oryza sativa Japonica Group	Q60EQ4	92.7%	Diamond
Arabidopsis thaliana	O23310	88.0%	Diamond
Kluyveromyces lactis NRRL Y-1140	P40914	85.2%	Diamond
Saccharomyces cerevisiae S288C	P13434	82.9%	Diamond
Dictyostelium discoideum	Q54WV0	80.6%	Diamond
Petromyzon marinus	P25210	78.9%	Diamond
Schizosaccharomyces pombe 972h-	P36611	70.5%	Diamond
Drosophila melanogaster	Q9VJQ5	67.5%	Diamond
Caenorhabditis elegans	O17286	61.7%	Diamond
Yarrowia lipolytica CLIB122	Q6CHS6	38.8%	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
C9orf43	protein-coding	257169
RGS3	protein-coding	5998
ALAD	protein-coding	210
HDHD3	protein-coding	81932
BSPRY	protein-coding	54836
WDR31	protein-coding	114987

Protein

Protein identifiers

DNA polymerase epsilon subunit 3 — Q9NRF9 (reviewed: Q9NRF9)

Alternative names: Arsenic-transactivated protein, Chromatin accessibility complex 17 kDa protein, DNA polymerase II subunit 3, DNA polymerase epsilon subunit p17

All UniProt accessions (1): Q9NRF9

UniProt curated annotations — full annotation on UniProt →

Function. Accessory component of the DNA polymerase epsilon complex. Participates in DNA repair and in chromosomal DNA replication. Forms a complex with CHRAC1 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome-remodeling activity of ISWI/SNF2H and ACF1. Does not enhance nucleosome sliding activity of the ACF-5 ISWI chromatin remodeling complex.

Subunit / interactions. Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4. Interaction with POLE4 is a prerequisite for further binding with POLE and POLE2. Heterodimer with CHRAC1; binds to DNA. Component of the CHRAC ISWI chromatin remodeling complex at least composed of SMARCA5/SNF2H, BAZ1A/ACF1, CHRAC1 and POLE3; the complex preferentially binds DNA through the CHRAC1-POLE3 heterodimer and possesses ATP-dependent nucleosome-remodeling activity. Within the complex, the heterodimer with CHRAC1 interacts with SMARCA5/SNF2H; the interaction is direct and enhances nucleosome sliding activity by the SMARCA5/SNF2H and BAZ1A/ACF1 interaction. Within the complex, the heterodimer with CHRAC1 interacts with BAZ1A/ACF1; the interactions are direct.

Subcellular location. Nucleus.

Tissue specificity. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

RefSeq proteins (3): NP_001265184, NP_001420648, NP_059139* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003958	CBFA_NFYB_domain	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR051377	DNA_Pol-Epsilon_Subunit	Family

Pfam: PF00808

Enzyme classification (BRENDA)

• EC 2.7.7.7 — DNA-directed DNA polymerase (BRENDA: 139 organisms, 372 substrates, 325 inhibitors, 281 Km, 239 kcat entries)

Substrate kinetics (BRENDA)

52 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DATP	0.0003–3.2	52
DCTP	0.0001–2.5	46
DTTP	0.0003–47.4	46
DGTP	0.0002–2.5	29
DEOXYNUCLEOSIDE TRIPHOSPHATE	0.0012–0.64	12
DNAN	—	7
7-DEAZA-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.0011–0.344	5
N1-METHYL-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.223–0.403	5
2-AMINOPURINE-2’-DEOXY-D-RIBOSE 5’-TRIPHOSPHATE	0.006–0.0144	2
2-THIO-DCTP	0.067–0.98	2
5-METHYL-DCTP	0.013–1.22	2
DAMP:DG	1.153–1.42	2
DCMP:DG	—	2
DGMP:DG	0.263–0.3511	2
DTMP:DG	1.26–1.43	2

UniProt features (15 total): sequence variant 3, sequence conflict 3, modified residue 3, compositionally biased region 2, initiator methionine 1, chain 1, region of interest 1, coiled-coil region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRF9-F1	85.72	0.58

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol; nucleoli

Antibody reliability (HPA): IH uncertain · IF approved

Functional residue map

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

Post-translational modifications (3)

Type	Positions
N-acetylalanine	2
Phosphothreonine	83
Phosphoserine	122

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 30; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

30 pathways:

ID	Pathway	Evidence
R-HSA-68962	Activation of the pre-replicative complex	—
R-HSA-73884	Base Excision Repair	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-73893	DNA Damage Bypass	—
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-69306	DNA Replication	—
R-HSA-69002	DNA Replication Pre-Initiation	—
R-HSA-68952	DNA replication initiation	—
R-HSA-5696400	Dual Incision in GG-NER	—
R-HSA-6782135	Dual incision in TC-NER	—
R-HSA-69206	G1/S Transition	—
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER	—
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER	—
R-HSA-5696399	Global Genome Nucleotide Excision Repair (GG-NER)	—
R-HSA-5685942	HDR through Homologous Recombination (HRR)	—
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	—
R-HSA-5693538	Homology Directed Repair	—
R-HSA-453279	Mitotic G1 phase and G1/S transition	—
R-HSA-5696398	Nucleotide Excision Repair	—
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair	—
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex	—
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway	—
R-HSA-73933	Resolution of Abasic Sites (AP sites)	—
R-HSA-69242	S Phase	—
R-HSA-69239	Synthesis of DNA	—
R-HSA-5656169	Termination of translesion DNA synthesis	—
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)	—
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	—

MSigDB gene sets: 300 (showing top): MORF_MTA1, REACTOME_DNA_REPLICATION, MORF_SMC1L1, MORF_UBE2I, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_HDAC1, MORF_UBE2N, MORF_RAD21, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MORF_HDAC2, KAUFFMANN_DNA_REPAIR_GENES, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, PUJANA_CHEK2_PCC_NETWORK

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261), leading strand elongation (GO:0006272), regulation of DNA replication (GO:0006275), nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), heterochromatin formation (GO:0031507), DNA biosynthetic process (GO:0071897)

GO Molecular Function (5): DNA-directed DNA polymerase activity (GO:0003887), chromatin DNA binding (GO:0031490), protein heterodimerization activity (GO:0046982), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), epsilon DNA polymerase complex (GO:0008622), CHRAC (GO:0008623), ATAC complex (GO:0140672), chromatin (GO:0000785)

Reactome top-level categories

15 top-level categories:

Category	Pathways
DNA Damage Bypass	2
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
DNA Repair	2
Nucleotide Excision Repair	2
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Synthesis of DNA	1
DNA Replication Pre-Initiation	1
G1/S Transition	1
Resolution of Abasic Sites (AP sites)	1
Cell Cycle, Mitotic	1
DNA Double-Strand Break Repair	1
Homology Directed Repair	1

GO top-level categories

34 GO namespaces:

Category	Terms
DNA metabolic process	2
DNA replication	2
chromatin organization	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
DNA biosynthetic process	1
DNA replication, synthesis of primer	1
DNA strand elongation involved in DNA replication	1
DNA replication, removal of RNA primer	1
regulation of DNA metabolic process	1
nucleosome organization	1
protein-DNA complex assembly	1
cellular response to stress	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
nucleic acid biosynthetic process	1
DNA polymerase activity	1
DNA binding	1
chromatin binding	1
protein dimerization activity	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear chromosome	1
DNA polymerase complex	1
nuclear protein-containing complex	1
ISWI-type complex	1
SAGA-type complex	1
chromosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
DNA-templated DNA replication	BP	direct assay
chromatin remodeling	BP	direct assay
negative regulation of transcription by RNA polymerase II	BP	direct assay
nucleosome assembly	BP	direct assay
regulation of DNA replication	BP	mutant phenotype
ATAC complex	CC	direct assay
epsilon DNA polymerase complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,236 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLE3	POLE4	Q9NR33	976
POLE3	CHRAC1	Q9NRG0	962
POLE3	POLE2	P56282	945
POLE3	BAZ1A	Q9NRL2	914
POLE3	POLE	Q07864	913
POLE3	SMARCA5	O60264	884
POLE3	SMARCA1	P28370	805
POLE3	RSF1	Q96T23	675
POLE3	NFYC	Q13952	675
POLE3	BAZ1B	Q9UIG0	669
POLE3	POLD2	P49005	664
POLE3	MBIP	Q9NS73	663
POLE3	TADA2A	O75478	616
POLE3	POLA2	Q14181	596
POLE3	H2AC20	Q16777	577

IntAct

Human interaction partners of POLE3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
CHRAC1	physical association	0.830	13
DRAP1	physical association	0.830	7
DR1	physical association	0.780	7
POLE4	physical association	0.770	5
POLE2	association	0.690	1
ORF	physical association	0.560	1
SMARCA5	association	0.530	1
ERI3	association	0.350	1

BioGRID (159 interactions; top human partners by supporting records): CHRAC1 (Two-hybrid; 9 records), SMARCA5 (Co-fractionation; 9 records), BAZ1A (Positive Genetic; 7 records), POLE (Co-fractionation; 6 records), POLE2 (Affinity Capture-MS; 6 records), POLE4 (Co-fractionation; 5 records), DR1 (Two-hybrid; 4 records), DRAP1 (Two-hybrid; 4 records), SMARCA1 (Co-fractionation; 3 records), C16orf72 (Negative Genetic; 2 records), YEATS2 (Affinity Capture-MS; 2 records), ANXA6 (Co-fractionation), APEH (Co-fractionation), APP (Reconstituted Complex), ARF1 (Positive Genetic)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
POLE3	“form complex”	“DNA polymerase epsilon”	binding

Protein complexes (CORUM) (7)

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

7 complexes by size:

Complex	Subunits	Members
★ RC complex, S-phase-specific	23	POLD4, POLE2, POLE4, CCNA2, CDK2, POLD2, POLD3, RFC2, POLE, RFC1, RFC5, RPA3, LIG1, PARP1, POLA1, POLD1, RFC3, RPA2, POLA2, POLE3, RFC4, RPA1, TOP1
★ DNA synthesome complex, breast cancer MCF7 cells	23	POLA2, POLD3, POLE4, PRIM1, RFC1, RPA1, PCNA, POLD4, POLE2, POLE3, RFC4, TOP1, POLA1, RFC2, RFC3, RFC5, RPA2, RPA3, TOP2A, POLD1, POLD2, POLE, PRIM2
★ DNA synthesome complex, breast cancer cells	20	POLD3, POLE4, RFC2, RFC3, POLA2, POLE3, LIG1, PARP1, PCNA, POLD2, PRIM1, PRIM2, RFC1, RFC4, POLD4, POLE, POLE2, RFC5, POLA1, POLD1
★ RC complex, G2/M-phase-specific	19	CCNB1, POLA1, POLA2, POLD2, RPA1, RPA2, CDK1, POLD3, RFC1, RFC2, RPA3, POLD1, POLD4, POLE, POLE3, PARP1, POLE2, POLE4, TOP1
ATAC complex, YEATS2-linked	14	SGF29, TADA3, UBAP2L, YEATS2, DR1, KAT2A, POLE3, TADA2A, WDR5, ZZZ3, KAT14, MAP3K7, MBIP, POLE4
HuCHRAC complex	4	POLE3, SMARCA5, BAZ1A, CHRAC1
★ DNA polymerase epsilon	4	POLE, POLE2, POLE3, POLE4

Disease & clinical

Genetic variants

Variant evidence for POLE3: 6 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 235):

Position(s)	Effect	Δscore	Sites
9:113408984–113408985	acceptor_loss	1.0000	6
9:113408994	acceptor_gain	1.0000
9:113409608–113409609	donor_loss	1.0000	5
9:113409612	donor_gain	1.0000
9:113409729–113409730	acceptor_loss	1.0000	6
9:113410053–113410054	donor_loss	1.0000	5
9:113408986	acceptor_gain	0.9900
9:113410141–113410142	acceptor_loss	0.9900	6
9:113410226–113410227	donor_loss	0.9900	4
9:113408981	acceptor_gain	0.9800

AlphaMissense

483 missense substitutions predicted likely pathogenic (of 985 scored), across 101 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
M76	9	0.928	0.997
D68	8	0.998	0.999
D7	8	0.993	0.999
F44	8	0.983	0.999
S42	8	0.960	0.999
F78	8	0.960	0.998
F81	8	0.933	0.995
R17	7	0.984	1.000
E6	7	0.955	0.996
E3	7	0.942	0.994
N53	7	0.917	0.996
C51	7	0.859	0.979
N9	7	0.857	0.990
P11	6	0.999	1.000
K20	6	0.993	0.998
K62	6	0.993	0.999
V45	6	0.992	0.999
K31	6	0.991	0.997
V69	6	0.985	0.999
V14	6	0.984	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.59e-07
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	9.31e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000281

Disease associations

OMIM: gene MIM:607267 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363042 (PROTEIN FAMILY), CHEMBL3833525 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.59	Kd	25.76	nM	CHEMBL5653589
7.30	ED50	49.95	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149031: Binding affinity to human POLE3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0258	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol A	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
beta-lapachone	decreases expression	1
arsenite	affects expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
K 7174	decreases expression	1
fenpyroximate	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
pyrimidifen	increases expression	1
abrine	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimycin A	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5052917	Binding	Binding affinity towards wild-type POLE3 overexpressed in human 293T cells measured after 1 hr by SDS-PAGE analysis	Novel sesquiterpenoid analogs

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3E7	Abcam HEK293T POLE3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for POLE3 across ~30M SureChEMBL compounds — explore on Sugi Predict.