TDP2

Summary

TDP2 (tyrosyl-DNA phosphodiesterase 2, HGNC:17768) is a protein-coding gene on chromosome 6p22.3, encoding Tyrosyl-DNA phosphodiesterase 2 (O95551). DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5’-phosphodiester bond, giving rise to DNA with a free 5’ phosphate. It is a selective cancer dependency (DepMap: 13.4% of cell lines).

This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors.

Source: NCBI Gene 51567 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive 23 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 98 total — 11 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 38 tissues, sQTL in 11 (q < 0.05)
• Phenotypes (HPO): 13
• ChEMBL bioactivity: 3 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 13.4% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.20 (unconstrained)
• MANE Select transcript: NM_016614

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17768
Approved symbol	TDP2
Name	tyrosyl-DNA phosphodiesterase 2
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111802
Ensembl biotype	protein_coding
OMIM	605764
Entrez	51567

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000378198

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 1, TSL 5: 1

ENST00000378198, ENST00000341060, ENST00000478285, ENST00000478507, ENST00000480495, ENST00000874523, ENST00000874524, ENST00000954493, ENST00001003522, ENST00001003523, ENST00001003524, ENST00001003525, ENST00001011895, ENST00001061347, ENST00001061349, ENST00001121300, ENST00001127386, ENST00001133591

RefSeq mRNA: 1 — MANE Select: NM_016614 NM_016614

CCDS: CCDS4557

Canonical transcript exons

ENST00000378198 — 7 exons

Exon	Start	End
ENSE00000615962	24658561	24658734
ENSE00000693189	24654412	24654530
ENSE00001476609	24649979	24651069
ENSE00001896291	24666698	24666899
ENSE00003592092	24666526	24666611
ENSE00003606958	24657812	24657903
ENSE00003680876	24652983	24653153

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.0020 / max 564.3900, expressed in 1815 samples.

Highest expression (Bgee): jejunal mucosa, mucosa of sigmoid colon, colonic mucosa, ileal mucosa, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TDP2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 11 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 49 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	3.0e-26	+0.38	6:24669717:T:C
Skin Sun Exposed Lower leg	eqtl	1.4e-19	+0.23	6:24697196:T:C
Muscle Skeletal	eqtl	1.4e-18	+0.24	6:24686063:C:A
Heart Atrial Appendage	eqtl	1.4e-12	-0.22	6:24584138:A:G
Skin Not Sun Exposed Suprapubic	eqtl	3.3e-12	+0.22	6:24697196:T:C
Testis	eqtl	9.2e-10	-1.35	6:24671780:T:C
Brain Caudate basal ganglia	eqtl	1.7e-09	-0.30	6:24640387:G:C
Brain Nucleus accumbens basal ganglia	eqtl	4.6e-09	-0.35	6:24650443:C:T
Pituitary	eqtl	2.6e-08	-0.28	6:24650503:T:G
Adipose Subcutaneous	eqtl	4.2e-08	+0.20	6:24669717:T:C
Brain Frontal Cortex BA9	eqtl	5.7e-08	-0.30	6:24650503:T:G
Cells EBV-transformed lymphocytes	eqtl	1.2e-07	-0.91	6:25159530:G:A
Brain Putamen basal ganglia	eqtl	1.4e-07	-0.32	6:24638512:G:T
Brain Cortex	eqtl	2.9e-07	-0.27	6:24650443:C:T
Brain Hypothalamus	eqtl	5.5e-06	-0.34	6:24650533:A:G
Thyroid	eqtl	8.4e-06	-0.15	6:24650443:C:T
Artery Aorta	eqtl	1.4e-05	-0.17	6:24650443:C:T
Whole Blood	sqtl	1.9e-05	-0.31	6:24668807:A:AT
Artery Tibial	eqtl	1.0e-04	-0.28	6:24726810:C:A
Whole Blood	eqtl	1.1e-04	-0.36	6:24651771:G:C

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
72195	18.9667	1808
72192	6.9081	1108
72196	1.0588	557
72193	0.9275	400
72191	0.7134	325
72194	0.3408	155
72198	0.0681	28
72199	0.0186	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.60	gold quality
colonic mucosa	UBERON:0000317	99.58	gold quality
ileal mucosa	UBERON:0000331	99.10	gold quality
rectum	UBERON:0001052	98.40	gold quality
duodenum	UBERON:0002114	98.39	gold quality
mucosa of transverse colon	UBERON:0004991	97.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.43	gold quality
palpebral conjunctiva	UBERON:0001812	97.31	gold quality
nephron tubule	UBERON:0001231	97.01	gold quality
islet of Langerhans	UBERON:0000006	96.80	gold quality
jejunum	UBERON:0002115	96.52	gold quality
germinal epithelium of ovary	UBERON:0001304	96.51	gold quality
secondary oocyte	CL:0000655	96.42	gold quality
visceral pleura	UBERON:0002401	96.26	gold quality
small intestine	UBERON:0002108	96.18	gold quality
transverse colon	UBERON:0001157	96.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.97	gold quality
parietal pleura	UBERON:0002400	95.93	gold quality
pleura	UBERON:0000977	95.84	gold quality
tibia	UBERON:0000979	95.74	gold quality
amniotic fluid	UBERON:0000173	95.58	gold quality
kidney epithelium	UBERON:0004819	95.58	gold quality
bronchial epithelial cell	CL:0002328	95.54	gold quality
seminal vesicle	UBERON:0000998	95.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.49	gold quality
colonic epithelium	UBERON:0000397	95.45	gold quality
cauda epididymis	UBERON:0004360	95.43	gold quality
epithelium of nasopharynx	UBERON:0001951	95.38	gold quality
blood	UBERON:0000178	95.36	gold quality
intestine	UBERON:0000160	95.32	gold quality
skin of hip	UBERON:0001554	95.21	gold quality
blood vessel layer	UBERON:0004797	95.08	gold quality
large intestine	UBERON:0000059	95.00	gold quality
pons	UBERON:0000988	94.92	gold quality
colon	UBERON:0001155	94.82	gold quality
renal glomerulus	UBERON:0000074	94.80	gold quality
caecum	UBERON:0001153	94.80	gold quality
substantia nigra pars compacta	UBERON:0001965	94.78	gold quality
corpus epididymis	UBERON:0004359	94.75	gold quality
upper leg skin	UBERON:0004262	94.64	gold quality
adult mammalian kidney	UBERON:0000082	94.59	gold quality
vermiform appendix	UBERON:0001154	94.58	gold quality
metanephric glomerulus	UBERON:0004736	94.53	gold quality
caput epididymis	UBERON:0004358	94.51	gold quality
adult organism	UBERON:0007023	94.51	gold quality
oral cavity	UBERON:0000167	94.48	gold quality
calcaneal tendon	UBERON:0003701	94.47	gold quality
superficial temporal artery	UBERON:0001614	94.37	gold quality
mammalian vulva	UBERON:0000997	94.36	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.20	gold quality
prostate gland	UBERON:0002367	94.18	gold quality
penis	UBERON:0000989	94.08	gold quality
kidney	UBERON:0002113	94.03	gold quality
epithelium of bronchus	UBERON:0002031	93.83	gold quality
urethra	UBERON:0000057	93.82	gold quality
heart right ventricle	UBERON:0002080	93.72	gold quality
bronchus	UBERON:0002185	93.67	gold quality
gall bladder	UBERON:0002110	93.66	gold quality
urinary bladder	UBERON:0001255	93.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.37	gold quality
stromal cell of endometrium	CL:0002255	93.31	gold quality
nasal cavity mucosa	UBERON:0001826	93.26	gold quality
pancreas	UBERON:0001264	93.25	gold quality
cortex of kidney	UBERON:0001225	93.16	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.16	gold quality
metanephros	UBERON:0000081	93.15	gold quality
leukocyte	CL:0000738	93.07	gold quality
monocyte	CL:0000576	93.00	gold quality
mononuclear cell	CL:0000842	92.98	gold quality
postcentral gyrus	UBERON:0002581	92.97	gold quality
lateral globus pallidus	UBERON:0002476	92.94	gold quality
middle temporal gyrus	UBERON:0002771	92.93	gold quality
lymph node	UBERON:0000029	92.90	gold quality
oocyte	CL:0000023	92.89	gold quality
myocardium	UBERON:0002349	92.72	gold quality
trabecular bone tissue	UBERON:0002483	92.67	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.62	gold quality
parotid gland	UBERON:0001831	92.59	gold quality
ganglionic eminence	UBERON:0004023	92.57	gold quality
sigmoid colon	UBERON:0001159	92.51	gold quality
decidua	UBERON:0002450	92.48	gold quality
renal medulla	UBERON:0000362	92.40	gold quality
cerebellum	UBERON:0002037	92.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.32	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.27	gold quality
cerebellar cortex	UBERON:0002129	92.23	gold quality
cerebellar hemisphere	UBERON:0002245	92.23	gold quality
lower lobe of lung	UBERON:0008949	92.23	gold quality
parietal lobe	UBERON:0001872	92.17	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.16	gold quality
bone marrow	UBERON:0002371	92.09	gold quality
cortical plate	UBERON:0005343	92.07	gold quality
endometrium	UBERON:0001295	91.94	gold quality
superior frontal gyrus	UBERON:0002661	91.94	gold quality
synovial joint	UBERON:0002217	91.92	gold quality
embryo	UBERON:0000922	91.85	gold quality
tibial artery	UBERON:0007610	91.83	gold quality
popliteal artery	UBERON:0002250	91.82	gold quality
cranial nerve II	UBERON:0000941	91.76	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	16.20
E-ANND-3	yes	7.18
E-GEOD-100618	no	474.14
E-GEOD-75367	no	286.13
E-MTAB-6524	no	96.32

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Small intestine	tissue	172.6	high
Colon	tissue	132.7	high
Rectum	tissue	119.7	high
Duodenum	tissue	113.1	high
Kidney	tissue	72.7	high
Prostate	tissue	53.0	medium
Liver	tissue	47.9	not detected
Lymph node	tissue	36.3	not detected
Tonsil	tissue	35.3	low
Thymus	tissue	34.9
Appendix	tissue	32.4	high
Choroid plexus	tissue	29.0
Putamen	tissue	28.6
Pancreas	tissue	27.8	low
Gallbladder	tissue	26.9	low
Postcentral gyrus	tissue	26.9
Heart muscle	tissue	26.4	not detected
Cerebellum	tissue	26.3	not detected
Spleen	tissue	26.3	not detected
Breast	tissue	25.6	low
Urinary bladder	tissue	25.5	low
Stomach 1	tissue	24.7	not detected
Locus coeruleus	tissue	24.6
Tongue	tissue	24.5
Nucleus accumbens	tissue	24.4
Parathyroid gland	tissue	24.2	not detected
Basal ganglia	tissue	24.2	not detected
Epididymis	tissue	23.9	low
Testis	tissue	23.6	medium
Ventral forebrain	tissue	23.3
Pons	tissue	23.1
Lung	tissue	23.1	low
Smooth muscle	tissue	23.0	not detected
Adipose tissue	tissue	22.9	not detected
Thalamus	tissue	22.6
Ovary	tissue	22.5	not detected
Superior colliculi	tissue	22.4
Midbrain	tissue	22.3
Adrenal gland	tissue	22.3	low
Septum	tissue	22.1
Hippocampal formation	tissue	21.8
Fallopian tube	tissue	21.3	not detected
Substantia nigra	tissue	20.8
Medulla oblongata	tissue	20.6
Bone marrow	tissue	20.6	not detected
Pituitary gland	tissue	20.5
Cerebral cortex	tissue	20.5	not detected
Seminal vesicle	tissue	20.5	not detected
Salivary gland	tissue	20.5	medium
Somatosensory cortex	tissue	20.5
Thyroid gland	tissue	20.3	not detected
Occipital cortex	tissue	20.2
Skin 1	tissue	19.9	not detected
Hippocampus	tissue	19.9	not detected
Periaqueductal gray	tissue	19.9
Hypothalamus	tissue	19.7
Cervix	tissue	19.4	not detected
Motor cortex	tissue	19.2
Prefrontal cortex	tissue	18.9
Placenta	tissue	18.9	low

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Anterior thalamic nucleus, ventral (33.7), Cerebellar cortex (28.5), Blood vessel (28.0), Lateral geniculate body (27.1), Precentral gyrus, middle (26.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting TDP2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 47 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-4477B	99.23	70.49	1733

Functional genomics

gnomAD constraint: pLI 1.84e-10, LOEUF 1.2, missense Z 0.324 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000378198 — one region, missense o/e 1.00. DepMap (CRISPR cell-line fitness): dependent in 13.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SK-ES-1 (-1.7), NB17 (-1.6), TUHR14TKB (-1.501), KP-N-YS (-1.474), NB-1 (-1.38), DBTRG-05MG (-1.289), HCC1187 (-1.276), SUP-M2 (-1.254), SNU-81 (-1.238), SCCH-196 (-1.231), OE21 (-1.203), EW-7 (-1.178), LU99 (-1.176), SISO (-1.144), A-375 (-1.123).

Literature-anchored findings (GeneRIF, showing 38)

• interacts with ETS1 and modulates its transcriptional function (PMID:12743594)
• a significant association with (TTRAP)on reading and spelling ability was observed (PMID:17597587)
• TTRAP is a novel PML nuclear body protein. (PMID:18706885)
• These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. (PMID:19023331)
• This is the first time that TTRAP has been shown to interact with HIV-1 integrase and facilitate lentiviral vector integration. (PMID:19580783)
• PhiC31 integrase interacts with TTRAP and inhibits the NFkappaB activation. (PMID:19757154)
• TTRAP is the first human 5’-tyrosyl DNA phosphodiesterase to be identified, and we suggest that this enzyme is denoted tyrosyl DNA phosphodiesterase-2 (TDP2). (PMID:19794497)
• an important mechanism for resistance to Top2-induced chromosome breakage and the possibility that TDP2 is a significant factor in cancer development and treatment (PMID:21030584)
• EAPII is an oncogenic factor and the activation of MAPK-ERK signaling pathway by EAPII may contribute to lung cancer development. (PMID:21478903)
• findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress. (PMID:21921940)
• both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. (PMID:22262880)
• Magnesium is indispensable for a 5’-tyrosyl DNA phosphodiesterase activity. (PMID:22405347)
• Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. (PMID:22822062)
• VPg unlinkase activity in different mammalian cell lines correlates with their differential expression of TDP2. (PMID:22908287)
• Mutations in the 5’-tyrosyl-DNA phosphodiesterase activity of TTRAP,in particular TTRAP(E152A), showed decreased inhibitory activity on cell growth. (PMID:23433115)
• TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. (PMID:24658003)
• Proteolytic degradation of Top2 enables the processing of Top2.DNA and Top2.RNA covalent complexes by TDP2. (PMID:24808172)
• This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents (PMID:24856239)
• Data show that DNA-repair enzyme TDP2 knockdown in HepG2 cells significantly delays the conversion of relaxed circular DNA (RC-DNA) to covalently closed circular (ccc) DNA. (PMID:25201958)
• Study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells’ DNA damage response and chemoresistance to Top2 inhibitors. (PMID:26701725)
• Both the genome instability and cell death of MRE11-null and MRE11-mutated H129N cells are significantly reversed by overexpression of Tdp2, an enzyme that eliminates covalent Top2 conjugates; thus, the essential role of Mre11 nuclease activity is likely to remove the DNA lesions. (PMID:27814490)
• TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. (PMID:28794467)
• These findings uncover a ZNF451-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2 cleavage complex. (PMID:28912134)
• Data suggest that tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are promising therapeutic targets and their inhibitors are expected to significantly synergize the effects of current anti-tumor therapies [Review]. (PMID:29216365)
• TDP2 re-localizes from the nucleus to the cytoplasm of EMCV infected cells. (PMID:29353210)
• lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2(S) isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria. (PMID:29438979)
• Data indicate that tyrosyl-DNA phosphodiesterase 2 (TDP2) alone does not remove DNA topoisomerase II (TOP2)-DNA complexes from genomic DNA in vitro and that depletion of TDP2 in cells does not slow the removal of TOP2-DNA complexes. (PMID:30011940)
• This article reviews TDP1 and TDP2 in the context of mitochondrial DNA repair. [review] (PMID:31226795)
• Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation. (PMID:32023921)
• TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands. (PMID:32277721)
• Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. (PMID:32356875)
• Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase 1 DNA-protein crosslinks and 3’-blocking lesions in the absence of tyrosyl-DNA phosphodiesterase 1 (TDP1). (PMID:32460231)
• Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23). (PMID:32651480)
• Untangling trapped topoisomerases with tyrosyl-DNA phosphodiesterases. (PMID:32653827)
• DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks. (PMID:33378676)
• A novel non-sense mutation in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by bilateral upward gaze; report of a case and review of the literature. (PMID:34606976)
• Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia. (PMID:37558815)
• Exploring the removal of Spo11 and topoisomerases from DNA breaks in S. cerevisiae by human Tyrosyl DNA Phosphodiesterase 2. (PMID:39236418)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tdp2b	ENSDARG00000035954
danio_rerio	tdp2a	ENSDARG00000069941
mus_musculus	Tdp2	ENSMUSG00000035958
rattus_norvegicus	Tdp2	ENSRNOG00000018246
caenorhabditis_elegans	tdpt-1	WBGENE00013405

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1860486) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal lymphopoiesis	1
abnormal immune system organ morphology	1
abnormal cell nucleus morphology	1
spleen atrophy	1
thymus atrophy	1
abnormal chromosome morphology	1
abnormal mitosis	1
abnormal immature B cell morphology	1
decreased double-positive T cell number	1
increased physiological sensitivity to xenobiotic	1
increased susceptibility to weight loss	1
abnormal erythroblast morphology	1
small intestinal villus atrophy	1
increased micronucleus incidence	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
Xenopus laevis	A5D8M0	87.4%	Diamond
Xenopus tropicalis	Q28FQ5	87.4%	Diamond
Bos taurus	A7YWI9	84.3%	Diamond
Caenorhabditis briggsae	A8XU68	79.6%	Diamond
Gallus gallus	F1NW29	63.0%	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
GPLD1	protein-coding	2822
ACOT13	protein-coding	55856
MRS2	protein-coding	57380
ALDH5A1	protein-coding	7915
KIAA0319	protein-coding	9856
DCDC2	protein-coding	51473
LINC02828	ncRNA	105374978
C6orf62	protein-coding	81688
GMNN	protein-coding	51053

Protein

Protein identifiers

Tyrosyl-DNA phosphodiesterase 2 — O95551 (reviewed: O95551)

Alternative names: 5’-tyrosyl-DNA phosphodiesterase, ETS1-associated protein 2, ETS1-associated protein II, TRAF and TNF receptor-associated protein, Tyrosyl-RNA phosphodiesterase, VPg unlinkase

All UniProt accessions (3): A0A384MDM5, O95551, X6R5A3

UniProt curated annotations — full annotation on UniProt →

Function. DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5’-phosphodiester bond, giving rise to DNA with a free 5’ phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. The 5’-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DNA double-strand breaks/DSBs without the need for nuclease activity, creating a ‘clean’ DSB with 5’-phosphate termini that are ready for ligation. Thereby, protects the transcription of many genes involved in neurological development and maintenance from the abortive activity of TOP2. Hydrolyzes 5’-phosphoglycolates on protruding 5’ ends on DSBs due to DNA damage by radiation and free radicals. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Acts as a regulator of ribosome biogenesis following stress. Also has 3’-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5’-tyrosyl-DNA phosphodiesterase in cells. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. (Microbial infection) Used by picornaviruses to remove the small polypeptide, VPg (virus Protein genome-linked, the primer for viral RNA synthesis), from the genomic RNA of the virus. Acts as a 5’-tyrosyl RNA phosphodiesterase and cleaves the covalent VPg-Tyr-RNA bond. This cleavage would play a role in viral replication and occur in viral replication vesicles, but would not act on viral mRNA.

Subunit / interactions. Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and ACVR1B/ALK4. (Microbial infection) Interacts with Hantaan hantavirus nucleoprotein. (Microbial infection) Interacts with Seoul hantavirus nucleoprotein.

Subcellular location. Nucleus. PML body. Nucleolus. Cytoplasm Cytoplasm.

Tissue specificity. Widely expressed. Highly expressed in various brain regions, including the frontal and occipital lobes, the hippocampus, the striatum and the cerebellum.

Post-translational modifications. Ubiquitinated by TRAF6.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23) [MIM:616949] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR23 patients manifest epilepsy, intellectual disability, and gait ataxia. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 magnesium or manganese ion per subunit.

Similarity. Belongs to the CCR4/nocturin family.

Isoforms (3)

UniProt ID	Names	Canonical?
O95551-1	1	yes
O95551-2	2
O95551-3	3

RefSeq proteins (1): NP_057698* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR051547	TDP2-like	Family

Pfam: PF03372, PF14555

Enzyme classification (BRENDA)

• EC 3.1.4.1 — phosphodiesterase I (BRENDA: 46 organisms, 274 substrates, 536 inhibitors, 102 Km, 61 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
P-NITROPHENYL PHENYLPHOSPHONATE	0.31–202	14
P-NITROPHENYLTHYMIDINE 5’-PHOSPHATE	0.043–6	14
BIS(4-NITROPHENYL)PHOSPHATE	1.2–22.2	9
P-NITROPHENYL ETHYL PHOSPHATE	1.7–73	9
BIS(P-NITROPHENYL) PHOSPHATE	0.25–14.4	6
BIS-P-NITROPHENYL PHOSPHATE	0.15–18.3	6
(5’-GATCTAAAAGACTT-3’)-PHOSPHOTYROSINE	0.0011–0.0048	4
DIADENOSINE 5’,5’’’-P1,P3-TRIPHOSPHATE	0.001–0.011	3
DIADENOSINE 5’,5’’’-P1,P4-TETRAPHOSPHATE	0.0006–0.008	3
P-NITROPHENYL 5’-THYMIDINE MONOPHOSPHATE	0.035–0.281	3
4-METHYLUMBELLIFERYL PHENYLPHOSPHONATE	4.9–8.2	2
4-METHYLUMBELLIFERYL THYMIDINE 5’-PHOSPHATE	0.22–2	2
4-NITROPHENYL URIDINE 5’-PHOSPHATE	0.19–0.41	2
NAD+	0.0096–0.03	2
P-NITROPHENYLPHOSPHORYLCHOLINE	1.53–3.33	2

UniProt features (70 total): strand 15, mutagenesis site 13, helix 10, region of interest 5, site 4, modified residue 4, sequence variant 4, sequence conflict 3, turn 3, cross-link 2, splice variant 2, binding site 2, chain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
6Q00	TDP2 UBA Domain Bound to Ubiquitin at 0.85 Angstroms Resolution, Crystal Form 1	X-RAY DIFFRACTION	0.85
6Q01	TDP2 UBA Domain Bound to Ubiquitin at 0.85 Angstroms Resolution, Crystal Form 2	X-RAY DIFFRACTION	0.85
5J3P	Crystal structure of the catalytic domain of human tyrosyl DNA phosphodiesterase 2	X-RAY DIFFRACTION	3.1
5INO	Human Tdp2 reaction product (5’-phosphorylated DNA)-Mg2+ complex	X-RAY DIFFRACTION	3.21
5J3S	Crystal structure of the catalytic domain of human tyrosyl DNA phosphodiesterase 2 in …	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95551-F1	85.61	0.73

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

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 (5)

Position	Role
178	interaction with 5’ end of substrate dna
297	interaction with 5’ end of substrate dna
315	interaction with 5’ end of substrate dna
351	interaction with 5’ end of substrate dna
262	proton donor/acceptor

Ligand- & substrate-binding residues (2)

Position	Role
122	Mg(2+)
152	Mg(2+)

Post-translational modifications (6)

Type	Positions
N-acetylmethionine	1
Phosphothreonine	88, 92
Phosphoserine	95
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	23, 82

Mutagenesis-validated functional residues (13)

Position	Phenotype
88	abolishes function, but retains ability to interact with smad3; when associated with a-92.
92	abolishes function, but retains ability to interact with smad3; when associated with a-88.
120	strongly reduced phosphodiesterase activity.
152	loss of phosphodiesterase activity.
178	strongly decreased phosphodiesterase activity.
206	loss of phosphodiesterase activity.
262	loss of phosphodiesterase activity.
305	decreased phosphodiesterase activity.
316	strongly decreased phosphodiesterase activity.
350	strongly decreased phosphodiesterase activity.
351	loss of phosphodiesterase activity. delayed poliovirus replication in host cells.
351	loss of phosphodiesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)	curated
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—

MSigDB gene sets: 191 (showing top): HORIUCHI_WTAP_TARGETS_DN, TGCGCANK_UNKNOWN, GOMF_NUCLEASE_ACTIVITY, GOBP_NEUROGENESIS, PATIL_LIVER_CANCER, MUELLER_PLURINET, GOBP_DNA_DAMAGE_RESPONSE, SCHLOSSER_SERUM_RESPONSE_DN, GRASEMANN_RETINOBLASTOMA_WITH_6P_AMPLIFICATION, REACTOME_DNA_REPAIR, BERENJENO_TRANSFORMED_BY_RHOA_UP, GOMF_SINGLE_STRANDED_DNA_BINDING, GOCC_NUCLEAR_BODY, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_DN, GOCC_PML_BODY

GO Biological Process (6): double-strand break repair (GO:0006302), cell surface receptor signaling pathway (GO:0007166), neuron development (GO:0048666), DNA repair (GO:0006281), DNA damage response (GO:0006974), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (13): magnesium ion binding (GO:0000287), single-stranded DNA binding (GO:0003697), transcription corepressor activity (GO:0003714), nuclease activity (GO:0004518), manganese ion binding (GO:0030145), tyrosyl-RNA phosphodiesterase activity (GO:0036317), 5’-tyrosyl-DNA phosphodiesterase activity (GO:0070260), DNA binding (GO:0003677), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), tyrosyl-DNA phosphodiesterase activity (GO:0070259)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), nuclear body (GO:0016604), PML body (GO:0016605)

Reactome top-level categories

2 top-level categories:

Category	Pathways
DNA Double-Strand Break Repair	1
DNA Repair	1

GO top-level categories

32 GO namespaces:

Category	Terms
phosphoric diester hydrolase activity	2
nuclear lumen	2
cellular anatomical structure	2
intracellular membraneless organelle	2
DNA repair	1
signal transduction	1
neuron differentiation	1
cell development	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
metal ion binding	1
DNA binding	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
catalytic activity, acting on a nucleic acid	1
transition metal ion binding	1
catalytic activity, acting on RNA	1
tyrosyl-DNA phosphodiesterase activity	1
nucleic acid binding	1
molecular_function	1
binding	1
catalytic activity	1
cation binding	1
catalytic activity, acting on DNA	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
nucleoplasm	1
nuclear body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 25 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
double-strand break repair	BP	direct assay
neuron development	BP	mutant phenotype
PML body	CC	direct assay
cytoplasm	CC	direct assay
nuclear body	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
5’-tyrosyl-DNA phosphodiesterase activity	MF	direct assay
magnesium ion binding	MF	direct assay
manganese ion binding	MF	direct assay
single-stranded DNA binding	MF	direct assay
tyrosyl-RNA phosphodiesterase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 989 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TDP2	ACOT13	Q9NPJ3	931
TDP2	KIAA0319	Q5VV43	925
TDP2	TDP1	Q9NUW8	906
TDP2	DCDC2	Q9UHG0	851
TDP2	ATM	Q13315	841
TDP2	TOP2A	P11388	762
TDP2	FKBP1A	P20071	760
TDP2	TOP1	P11387	741
TDP2	ZNF451	Q9Y4E5	715
TDP2	SPRTN	Q9H040	713
TDP2	APEX1	P27695	694
TDP2	DNAAF4	Q8WXU2	687
TDP2	TOP2B	Q02880	680
TDP2	HTT	P42858	668
TDP2	PNKP	Q96T60	658

IntAct

Human interaction partners of TDP2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

27 partners by confidence:

Partner	Interaction type	MIscore	Records
ATXN3	physical association	0.560	3
BLK	physical association	0.560	3
DNM2	physical association	0.560	3
C19orf25	association	0.530	1
BTBD2	physical association	0.490	2
DVL2	physical association	0.490	2
GOLGA2	physical association	0.490	2
TFIP11	physical association	0.490	2
SRPK2	phosphorylation reaction	0.440	1
E6	physical association	0.370	11
AKAP9	physical association	0.370	1
ATP5MC2	physical association	0.370	1
ATXN1	physical association	0.370	1
C2orf88	physical association	0.370	1
DLX3	physical association	0.370	1
ENTREP1	physical association	0.370	1
EPS8	physical association	0.370	1
ETS1	physical association	0.370	1
JAM2	physical association	0.370	1
MAPK6	physical association	0.370	1
PSEN1	physical association	0.370	1
RAB11A	physical association	0.370	1
SKIL	physical association	0.370	1
SMAD3	physical association	0.370	1
SNX13	physical association	0.370	1
TAP1	physical association	0.370	1
SUMO3	physical association	0.000	1

BioGRID (112 interactions; top human partners by supporting records): ETS1 (Two-hybrid; 4 records), AZIN1 (Affinity Capture-MS; 3 records), TCEAL1 (Affinity Capture-MS; 3 records), CD40 (Two-hybrid; 2 records), GORASP1 (Affinity Capture-MS; 2 records), LYPD4 (Affinity Capture-MS; 2 records), PARK7 (Affinity Capture-Western; 2 records), PLA2G10 (Affinity Capture-MS; 2 records), RSBN1 (Affinity Capture-MS; 2 records), SUMO1 (Two-hybrid; 2 records), SUMO2 (Two-hybrid; 2 records), SUMO3 (Two-hybrid; 2 records), TNFRSF1B (Affinity Capture-Western; 2 records), TP53 (Proximity Label-MS; 2 records), ACP1 (Affinity Capture-MS)

SIGNOR signaling

showing 4 of 6 signaling interactions:

A	Effect	B	Mechanism
ACVR1B	“up-regulates activity”	TDP2	phosphorylation
TDP2	“up-regulates activity”	TRAF6	binding
MAPK6	“up-regulates activity”	TDP2	phosphorylation
TRAF6	“up-regulates activity”	TDP2	ubiquitination

Disease & clinical

Genetic variants

Variant evidence for TDP2: 98 ClinVar records (13 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	2
Uncertain significance	51
Likely benign	14
Benign	5

Top pathogenic / likely-pathogenic (13)

Showing all 13 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
2041505	NM_016614.3(TDP2):c.400C>T (p.Arg134Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
620174	NM_016614.3(TDP2):c.389C>G (p.Ser130Ter)	Pathogenic	criteria provided, single submitter	1
812705	NM_016614.3(TDP2):c.636+3_636+6del	Pathogenic	criteria provided, single submitter	1
1323684	NM_016614.3(TDP2):c.650del (p.Gly217fs)	Pathogenic	criteria provided, single submitter	1
2139718	NM_016614.3(TDP2):c.390dup (p.Glu131fs)	Pathogenic	criteria provided, single submitter	1
2197639	NM_016614.3(TDP2):c.392_395del (p.Glu131fs)	Pathogenic	criteria provided, single submitter	1
2442386	NM_016614.3(TDP2):c.949C>T (p.Arg317Ter)	Pathogenic	criteria provided, single submitter	1
2598969	NM_016614.3(TDP2):c.580_581del (p.Gln194fs)	Pathogenic	criteria provided, single submitter	1
4753868	NM_016614.3(TDP2):c.591del (p.Pro198fs)	Pathogenic	criteria provided, single submitter	1
1325184	NM_016614.3(TDP2):c.635_636+2del	Likely pathogenic	criteria provided, single submitter	1
4852415	NM_016614.3(TDP2):c.560C>A (p.Ser187Ter)	Likely pathogenic	criteria provided, single submitter	1
226424	NM_016614.3(TDP2):c.425+1G>A	Pathogenic	no assertion criteria provided	3
226425	NM_016614.3(TDP2):c.413_414delinsAA (p.Ser138Ter)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore TDP2’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; 31 predictions of 464):

Position(s)	Effect	Δscore	Sites
6:24652981–24652982	donor_loss	1.0000	3
6:24653154–24653155	acceptor_loss	1.0000	6
6:24654531–24654532	acceptor_loss	1.0000	5
6:24654541	acceptor_gain	1.0000
6:24651070–24651071	acceptor_loss	0.9900	6
6:24652981–24652982	donor_loss	0.9900	2
6:24653158	acceptor_gain	0.9900
6:24653161	acceptor_gain	0.9900
6:24654410–24654411	donor_loss	0.9900	5
6:24654435	donor_gain	0.9900

AlphaMissense

698 missense substitutions predicted likely pathogenic (of 2,383 scored), across 180 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
M204	9	0.940	0.988
N120	8	0.993	0.997
H351	8	0.992	0.997
D350	8	0.991	0.997
D262	8	0.989	0.998
H226	8	0.988	0.996
N302	8	0.988	0.997
D316	8	0.987	0.995
N264	8	0.975	0.998
D282	8	0.970	0.989
S229	8	0.965	0.996
S349	8	0.959	0.998
D122	8	0.956	0.985
F315	8	0.946	0.995
D298	8	0.934	0.981
N304	8	0.929	0.994
F32	8	0.918	0.989
F259	8	0.880	0.976
D125	8	0.838	0.900
D146	8	0.811	0.948

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

6 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.13e-08
Colon Adenocarcinoma (validation)	favorable	5.31e-05
Rectum Adenocarcinoma (validation)	unfavorable	7.97e-05
Ovary Serous Cystadenocarcinoma (TCGA)	favorable	0.0003
Skin Cutaneous Melanoma (TCGA)	unfavorable	0.000328
Prostate Adenocarcinoma (TCGA)	unfavorable	0.000504

Disease associations

OMIM: gene MIM:605764 | disease phenotypes: MIM:616949

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
spinocerebellar ataxia, autosomal recessive 23	Strong	Autosomal recessive	5

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 23	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (9 panels, 9 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

9 panels:

Panel	Rating
Ataxia and cerebellar anomalies - childhood onset	green
DDG2P	green
Early onset or syndromic epilepsy	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (2): spinocerebellar ataxia, autosomal recessive 23 (MONDO:0014846), cerebellar ataxia (MONDO:0000437)

Orphanet (2): Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency (Orphanet:404493), Rare ataxia (Orphanet:102002)

HPO phenotypes

13 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001262	Excessive daytime somnolence
HP:0001290	Generalized hypotonia
HP:0001875	Decreased total neutrophil count
HP:0001999	Abnormal facial shape
HP:0002902	Hyponatremia
HP:0003388	Easy fatigability
HP:0011675	Arrhythmia

GWAS associations

1 associations:

Study	Trait	p-value
GCST003209_6	Colorectal or endometrial cancer	2e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004230	endometrial neoplasm

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2169736 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 37,785 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL265502	SURAMIN	3	37,133
CHEMBL15192	LAPACHONE	2	606
CHEMBL126159	LMP-744	1	46

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

448 measured of 678 human assays (716 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[3-[3-(4-chlorophenyl)-8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl]phenyl]boronic acid	IC50	3.85 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
[3-[4-(8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl)phenoxy]phenyl]boronic acid	IC50	5.01 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
N-[3-[3-(4-chlorophenyl)-8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl]phenyl]methanesulfonamide	IC50	6.09 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4441013	IC50	6.1 nM
N-[4-[3-(4-chlorophenyl)-8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl]phenyl]methanesulfonamide	IC50	6.49 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4572376	IC50	6.5 nM
3-(4-chlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	7.25 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4436202	IC50	7.3 nM
2,4-dioxo-10-[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]phenyl]-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	8.28 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
20-[3-(2-hydroxyethylamino)propyl]-15,16-dimethoxy-5,7-dioxa-20-azapentacyclo[10.8.0.02,10.04,8.013,18]icosa-1(12),2,4(8),9,13,15,17-heptaene-11,19-dione	KD	11 nM	US-20240287089: Preparation and Uses of 7-Azaindenoisoquinolines
3-(3,4-dichlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	13.6 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4587441	IC50	14 nM
3-(3-chlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	19.8 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4520052	IC50	20 nM
4-methoxy-N-(6-methoxy-4H-indeno[1,2-d][1,3]thiazol-2-yl)benzamide	IC50	23 nM
3-(4-chlorophenyl)-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	32.8 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4560735	IC50	33 nM
CHEMBL4468174	IC50	33 nM
10-(4-hydroxyphenyl)-2,4-dioxo-3-phenyl-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	33.1 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-3-yl]benzamide	IC50	35 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4555612	IC50	35 nM
methyl 3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-3-yl]benzoate	IC50	38 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4521151	IC50	38 nM
[3-[[4-(8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]phenyl]boronic acid	IC50	39 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
2,4-dioxo-10-[4-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy]phenyl]-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	47 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
phenyl N-[4-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-3-yl]phenyl]carbamate	IC50	59 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
3-(4-bromophenyl)-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	64.7 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4457155	IC50	65 nM
CHEMBL4546104	IC50	70 nM
3-(4-fluorophenyl)-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	70.4 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
O-methyl 3-chloro-5-[1-(3-chloro-4-methoxy-5-methoxycarbothioylphenyl)-6-methoxy-6-sulfanylidenehex-1-enyl]-2-methoxybenzenecarbothioate	KD	109 nM	US-20240287089: Preparation and Uses of 7-Azaindenoisoquinolines
phenyl N-[3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-3-yl]phenyl]carbamate	IC50	119 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
3-[4-[(diphenoxyphosphorylamino)methyl]phenyl]-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	119 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4518508	IC50	130 nM
3-[[4-(8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]benzoic acid	IC50	131 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4576353	IC50	150 nM
methyl 3-[[4-(8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]benzoate	IC50	153 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
3-[4-(diphenoxyphosphorylamino)phenyl]-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	185 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
3-[4-(8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl)phenoxy]benzoic acid	IC50	186 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4557001	IC50	190 nM
2,4-dioxo-10-(4-phenylmethoxyphenyl)-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	196 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4464179	IC50	200 nM
[4-[[4-(8-cyano-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]phenyl]boronic acid	IC50	239 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4471861	IC50	270 nM
3-(4-chlorophenyl)-2,4-dioxo-10-phenyl-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	274 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
3-[3-(diphenoxyphosphorylamino)phenyl]-10-(4-hydroxyphenyl)-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	277 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4536546	IC50	300 nM
2,4-dioxo-10-(3-phenoxyphenyl)-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	301 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
10-(4-hydroxyphenyl)-3-methyl-2,4-dioxo-1,10a-dihydropyrimido[4,5-b]quinoline-8-carbonitrile	IC50	317 nM	US-10617706: Compounds for cancer chemotherapeutic sensitization
CHEMBL4444838	IC50	320 nM

ChEMBL bioactivities

266 potent at pChembl≥5 of 533 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.41	IC50	3.85	nM	CHEMBL5923878
8.30	IC50	5.01	nM	CHEMBL5821949
8.21	IC50	6.1	nM	CHEMBL4441013
8.21	IC50	6.09	nM	CHEMBL5815522
8.19	IC50	6.5	nM	CHEMBL4572376
8.19	IC50	6.49	nM	CHEMBL5942240
8.14	IC50	7.3	nM	CHEMBL4436202
8.14	IC50	7.25	nM	CHEMBL5943540
8.08	IC50	8.28	nM	CHEMBL6011555
7.87	IC50	13.6	nM	CHEMBL6008959
7.85	IC50	14	nM	CHEMBL4587441
7.70	IC50	20	nM	CHEMBL4520052
7.70	IC50	19.8	nM	CHEMBL5747346
7.52	EC50	30	nM	CHEMBL2420474
7.48	IC50	33	nM	CHEMBL4560735
7.48	IC50	33	nM	CHEMBL4468174
7.48	IC50	33.1	nM	CHEMBL5794235
7.48	IC50	32.8	nM	CHEMBL6032828
7.46	IC50	35	nM	CHEMBL4555612
7.46	IC50	35	nM	CHEMBL5875928
7.42	IC50	38	nM	CHEMBL4521151
7.42	IC50	38	nM	CHEMBL5963431
7.41	IC50	39	nM	CHEMBL5797270
7.40	EC50	40	nM	CHEMBL2420480
7.40	IC50	40	nM	CHEMBL4470500
7.39	IC50	41	nM	CHEMBL2420480
7.38	IC50	42	nM	CHEMBL2420507
7.33	IC50	47	nM	CHEMBL5913356
7.30	EC50	50	nM	CHEMBL2420507
7.30	EC50	50	nM	CHEMBL2420481
7.23	IC50	59	nM	CHEMBL5968903
7.19	IC50	65	nM	CHEMBL4457155
7.19	IC50	64.7	nM	CHEMBL5975468
7.16	IC50	70	nM	CHEMBL4546104
7.15	IC50	70.4	nM	CHEMBL5751691
7.05	EC50	90	nM	CHEMBL2420472
7.05	EC50	90	nM	CHEMBL2420465
6.92	EC50	120	nM	CHEMBL2420614
6.92	IC50	119	nM	CHEMBL5796252
6.92	IC50	119	nM	CHEMBL5976026
6.89	IC50	130	nM	CHEMBL4518508
6.88	IC50	131	nM	CHEMBL6050161
6.85	IC50	140	nM	CHEMBL2420465
6.82	EC50	150	nM	CHEMBL2420610
6.82	IC50	150	nM	CHEMBL4576353
6.82	IC50	153	nM	CHEMBL5764329
6.79	IC50	161.1	nM	CHEMBL1325945
6.73	IC50	186	nM	CHEMBL5756305
6.73	IC50	185	nM	CHEMBL6037182
6.72	IC50	190	nM	CHEMBL4557001

PubChem BioAssay actives

176 with measured affinity, of 652 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
N-[3-[3-(4-chlorophenyl)-8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl]phenyl]methanesulfonamide	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0061	uM
N-[4-[3-(4-chlorophenyl)-8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl]phenyl]methanesulfonamide	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0065	uM
3-(4-chlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0073	uM
3-(3,4-dichlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0140	uM
3-(3-chlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0200	uM
2,4-dioxo-10-[3-(tetrazol-1-yl)phenyl]-1,4a,5,5a,6,7,8,9,9a,10a-decahydropyrimido[4,5-b]quinoline-8-carbonitrile	1801792: TDP2 Assays with Whole Cell Extracts from Article 10.1021/acschembio.5b01047: “Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.”	ic50	0.0250	uM
N-[3-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenyl]methanesulfonamide	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0300	uM
10-(4-hydroxyphenyl)-2,4-dioxo-3-phenylpyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0330	uM
3-(4-chlorophenyl)-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0330	uM
3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinolin-3-yl]benzamide	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0350	uM
methyl 3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinolin-3-yl]benzoate	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0380	uM
7-amino-5-imino-1H-quinoline-2,8-dione	1574190: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0400	uM
2,4-dioxo-10-[3-(2H-tetrazol-5-yl)phenyl]pyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0400	uM
10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0420	uM
3-[4-(3,4-dimethoxyphenyl)thiophen-2-yl]-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0500	uM
10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1801792: TDP2 Assays with Whole Cell Extracts from Article 10.1021/acschembio.5b01047: “Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.”	ic50	0.0620	uM
3-(4-bromophenyl)-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0650	uM
3-(4-fluorophenyl)-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0700	uM
10-(3-aminophenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0900	uM
1,6-dimethyl-3-(4-phenylthiophen-2-yl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.1200	uM
3-[[4-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]benzoic acid	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.1300	uM
methyl 3-[[4-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]benzoate	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.1500	uM
1,6-dimethyl-3-naphthalen-2-ylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.1500	uM
2,4-dioxo-10-phenylpyrimido[4,5-b]quinoline-8-carbonitrile	1801792: TDP2 Assays with Whole Cell Extracts from Article 10.1021/acschembio.5b01047: “Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.”	ic50	0.1800	uM
3-[4-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenoxy]benzoic acid	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.1900	uM
2,4-dioxo-10-(4-phenylmethoxyphenyl)pyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.2000	uM
3-(4-bromothiophen-2-yl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2000	uM
1,6-dimethyl-3-(4-methylthiophen-2-yl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2500	uM
10-[3-(hydroxymethyl)phenyl]-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2500	uM
1,6-dimethyl-3-[4-(trifluoromethoxy)phenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2600	uM
3-(4-chlorophenyl)-2,4-dioxo-10-phenylpyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.2700	uM
3-(4-ethylphenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2800	uM
3-(4-ethylphenyl)-6-methyl-1-propylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2800	uM
1,6-dimethyl-3-(4-methylphenyl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2900	uM
3-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)benzenesulfonamide	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2900	uM
2,4-dioxo-10-(3-phenoxyphenyl)pyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.3000	uM
1-ethyl-3-(4-ethylphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3000	uM
10-(4-hydroxyphenyl)-3-methyl-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.3200	uM
10-(3-hydroxy-4-methoxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3200	uM
1,6-dimethyl-3-[4-(trifluoromethyl)phenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3300	uM
1-(cyclopropylmethyl)-3-(4-ethylphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3600	uM
3-cyclopropyl-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3700	uM
10-(1H-indazol-4-yl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3700	uM
2,4-dioxo-10-(3-phenylmethoxyphenyl)pyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.3800	uM
1,6-dimethyl-3-(3-methylphenyl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4000	uM
3-(4-chlorophenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4300	uM
1,6-dimethyl-3-(oxan-4-yl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4300	uM
10-(3-methoxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4700	uM
8-chloro-10-(3-hydroxyphenyl)pyrimido[4,5-b]quinoline-2,4-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4800	uM
1,6-dimethyl-3-propylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.5100	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
lead acetate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	decreases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases response to substance, increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Menthol	increases expression	1
Quercetin	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
beta-Naphthoflavone	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

30 unique, capped per target: 30 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2174998	Binding	Inhibition of recombinant Tdp2	5-Arylidenethioxothiazolidinones as inhibitors of tyrosyl-DNA phosphodiesterase I. — *J Med Chem*

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2IB	Abcam HeLa TDP2 KO	Cancer cell line	Female
CVCL_E2LQ	HAP1 TDP2 (-) 2	Cancer cell line	Male
CVCL_F1KQ	DT40-TDP2(-/-/-) hTDP2	Cancer cell line	Female
CVCL_F1KR	DT40-TDP2(-/-/-) hTDP2 D262A	Cancer cell line	Female
CVCL_XU14	HAP1 TDP2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 150 trials:

NCT	Phase	Status	Title
NCT00950196	Phase 4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	Phase 4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT01970098	Phase 3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	Phase 3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	Phase 3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	Phase 3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	Phase 3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	Phase 3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	Phase 3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	Phase 3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	Phase 3	ACTIVE_NOT_RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00034242	Phase 2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	Phase 2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	Phase 2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	Phase 2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	Phase 2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	Phase 2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	Phase 2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	Phase 2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	Phase 2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	Phase 2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT00683943	Phase 1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	Phase 1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	Phase 1	UNKNOWN	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01104649	Phase 2/3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT02960893	Phase 2/3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT00244361	Phase 1/2	COMPLETED	Effectiveness of Rituximab in Pediatric OMS Patients.
NCT01649687	Phase 1/2	COMPLETED	Treatment of Cerebellar Ataxia With Mesenchymal Stem Cells
NCT01958177	Phase 1/2	UNKNOWN	Clinical Study to Evaluate the Safety and Efficacy BMMNC in Cerebellar Ataxia
NCT02829268	Phase 1/2	COMPLETED	A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00006492	Not specified	COMPLETED	Gluten-Free Diet in Patients With Gluten Sensitivity and Cerebellar Ataxia
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00272272	Not specified	COMPLETED	Fall Prevention in a Geriatric Nursing Home Setting Using the Music of Nolwenn Leroy
NCT00654251	Not specified	COMPLETED	Measuring Neurological Impairment and Functional Visual Assessment In Spinocerebellar Ataxias
NCT00692861	Not specified	COMPLETED	Autoimmunity in Neurologic Complications of Celiac Disease
NCT01037777	Not specified	COMPLETED	RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7
NCT01060371	Not specified	RECRUITING	Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias
NCT01307176	Not specified	COMPLETED	Exercise Training Program for Cerebellar Ataxia
NCT01428531	Not specified	COMPLETED	Special Drug Use Investigation for Arixtra® (Fondaparinux) Venous Thromboembolism Treatment
NCT01428544	Not specified	COMPLETED	Special Drug Use Investigation (Retrospective) for Arixtra® (Fondaparinux) Venous Thromboembolism Treatment (Over 100kg)
NCT01488461	Not specified	COMPLETED	Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias
NCT01845883	Not specified	WITHDRAWN	Perceptual Decision Making Under Conditions of Visual Uncertainty
NCT01975909	Not specified	COMPLETED	Transcranial Magnetic Stimulation in Spino-Cerebellar Ataxia
NCT01983631	Not specified	COMPLETED	The Effect of Whole Body Vibration Training on Neuromuscular Property in Individuals With Ataxia
NCT02103075	Not specified	COMPLETED	Neuromuscular Electrical Stimulation on Median Nerve Facilitates Low Motor Cortex Excitability in Human With Spinocerebellar Ataxia
NCT02400528	Not specified	UNKNOWN	Prospective Cohort Follow-up of French Patients With Profound and Multiple Disabilities: Healthcare Pathways and Quality of Life Among Patients and Their Families
NCT02440763	Not specified	RECRUITING	The EUROSCA Natural History Study
NCT02488031	Not specified	COMPLETED	Functional and Structural Imaging and Motor Control in Spinocerebellar Ataxia
NCT02741440	Not specified	ACTIVE_NOT_RECRUITING	Natural History of Spinocerebellar Ataxia Type 7 (SCA7)
NCT02841553	Not specified	RECRUITING	Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study
NCT02867969	Not specified	UNKNOWN	Slowing Down Disease Progression in Premanifest SCA: a Piloting Interventional Exergame Trial
NCT02874911	Not specified	COMPLETED	Coordination Training With Complete Body Video Games in Children and Adults With Degenerative Ataxias
NCT02887703	Not specified	COMPLETED	Augmenting Balance in Individuals With Cerebellar Ataxias
NCT02900508	Not specified	COMPLETED	Virtual Reality-based Training in Cerebellar Ataxia
NCT02903290	Not specified	COMPLETED	Longitudinal Monitoring of Energy Expenditure, Dynamic Stability and Fatigue During Gait in Patients With Cerebellar Ataxia Gene
NCT02977377	Not specified	COMPLETED	The Effects Of Whole Body Vibration On Postural Control In Patients With Ataxia
NCT03120013	Not specified	COMPLETED	Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TDP2 across ~30M SureChEMBL compounds — explore on Sugi Predict.