TOP2A

Summary

TOP2A (DNA topoisomerase II alpha, HGNC:11989) is a protein-coding gene on chromosome 17q21.2, encoding DNA topoisomerase 2-alpha (P11388). Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand. In precision oncology, TOP2A EXPRESSION confers sensitivity to Doxorubicin in Breast Cancer (CIViC Level B). It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia.

Source: NCBI Gene 7153 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 160 total
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_001067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11989
Approved symbol	TOP2A
Name	DNA topoisomerase II alpha
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	TOP2alpha, TOPIIA
Ensembl gene	ENSG00000131747
Ensembl biotype	protein_coding
OMIM	126430
Entrez	7153

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000423485, ENST00000577541, ENST00000577706, ENST00000578412, ENST00000581055, ENST00000917864, ENST00000917865

RefSeq mRNA: 1 — MANE Select: NM_001067 NM_001067

CCDS: CCDS45672

Canonical transcript exons

ENST00000423485 — 35 exons

Exon	Start	End
ENSE00000900568	40392585	40392737
ENSE00000900569	40395449	40395539
ENSE00000900570	40396283	40396465
ENSE00000900573	40399040	40399131
ENSE00000900574	40399872	40400067
ENSE00000900575	40400209	40400409
ENSE00000900576	40400529	40400663
ENSE00000900577	40400850	40401081
ENSE00000900578	40402906	40403054
ENSE00000900579	40404152	40404273
ENSE00000900580	40404377	40404491
ENSE00000900581	40404791	40404883
ENSE00000900583	40406584	40406689
ENSE00000900584	40406832	40406942
ENSE00000900588	40407967	40408124
ENSE00000900590	40408492	40408630
ENSE00000900596	40411109	40411246
ENSE00001182061	40391506	40391640
ENSE00001182144	40412759	40412971
ENSE00001182163	40416005	40416068
ENSE00001182168	40416422	40416512
ENSE00001363882	40411645	40411818
ENSE00001368747	40411354	40411455
ENSE00001533405	40392068	40392111
ENSE00001533409	40392218	40392341
ENSE00001533480	40413195	40413292
ENSE00001594286	40407549	40407674
ENSE00001633936	40406384	40406493
ENSE00001750547	40388525	40389647
ENSE00001780806	40417771	40417896
ENSE00003459573	40389965	40390164
ENSE00003507255	40416740	40416895
ENSE00003526356	40398773	40398937
ENSE00003664321	40398558	40398641
ENSE00003788736	40413480	40413625

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.3822 / max 2345.5880, expressed in 1592 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165716	68.6659	1578
165717	3.1792	878
165710	0.3398	24
165714	0.1972	95

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.62	gold quality
ganglionic eminence	UBERON:0004023	98.94	gold quality
secondary oocyte	CL:0000655	98.82	gold quality
embryo	UBERON:0000922	98.54	gold quality
right testis	UBERON:0004534	95.39	gold quality
oocyte	CL:0000023	95.26	gold quality
left testis	UBERON:0004533	94.51	gold quality
bone marrow	UBERON:0002371	93.80	gold quality
trabecular bone tissue	UBERON:0002483	93.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.68	gold quality
testis	UBERON:0000473	93.67	gold quality
bone marrow cell	CL:0002092	93.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.58	gold quality
endometrium epithelium	UBERON:0004811	91.44	gold quality
stromal cell of endometrium	CL:0002255	91.41	gold quality
thymus	UBERON:0002370	91.30	gold quality
mucosa of transverse colon	UBERON:0004991	91.07	gold quality
lower esophagus mucosa	UBERON:0035834	90.88	gold quality
oral cavity	UBERON:0000167	90.39	gold quality
adrenal tissue	UBERON:0018303	90.00	gold quality
vermiform appendix	UBERON:0001154	88.96	gold quality
gingival epithelium	UBERON:0001949	88.51	gold quality
rectum	UBERON:0001052	88.19	gold quality
gingiva	UBERON:0001828	87.95	gold quality
pylorus	UBERON:0001166	87.94	gold quality
sperm	CL:0000019	86.78	gold quality
esophagus squamous epithelium	UBERON:0006920	86.78	gold quality
esophagus mucosa	UBERON:0002469	86.59	gold quality
male germ cell	CL:0000015	86.43	gold quality
caecum	UBERON:0001153	86.34	gold quality

Single-cell (SCXA)

Detected in 54 experiment(s), a significant marker in 48.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	5407.73
E-MTAB-6819	yes	3364.02
E-GEOD-93593	yes	2856.31
E-MTAB-8894	yes	2778.54
E-MTAB-11121	yes	2730.22
E-MTAB-6379	yes	2111.64
E-HCAD-56	yes	1810.73
E-GEOD-98556	yes	1799.00
E-MTAB-10485	yes	1685.22
E-MTAB-10662	yes	1572.91
E-ENAD-17	yes	1550.14
E-CURD-79	yes	1470.90
E-HCAD-31	yes	1418.31
E-ENAD-20	yes	1318.32
E-GEOD-124858	yes	1259.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, CEBPA, E2F1, E2F4, NFYB, UHRF1, YBX1

miRNA regulators (miRDB)

65 targeting TOP2A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-548A-3P	99.76	70.58	3524

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• The heat-induced transition of TOP2A requires both Mg2+ and DNA, is stable for several hours and leads to loss of DNA strand activity. A second transition correlates with a drop in the level of DNA scission, followed by religation at high temperatures. (PMID:11444988)
• increased expression appears to be part of malignant cells’ phenotype in recurrent colon cancers (PMID:11862483)
• topo II is not an immobile, structural component of the chromosomal scaffold or the interphase karyoskeleton, but rather a dynamic interaction partner of such structures. (PMID:11927602)
• The role of topoisomerase II in the excision of DNA loop domains during apoptosis. (PMID:11940566)
• Topoisomerase II alpha represents a reliable alternative to monoclonal antibody MIB-1 as a proliferation marker in human meningiomas. (PMID:11958416)
• Overexpression of topoisomerase IIalpha induced by mutant p53 is associated with aggressive carcinogenesis in non-small cell lung carcinoma (PMID:12001123)
• Transcriptional regulation of the human topoisomerase IIalpha gene (PMID:12014628)
• Redox control of cell cycle-coupled topoisomerase II alpha gene expression (PMID:12078518)
• The ATP-operated clamp of human DNA topoisomerase IIalpha: model for DNA-dependent ATPase activity. (PMID:12079377)
• presence of dna topoisomerase II in different testicular tumor types (PMID:12237772)
• Co-localizes with centromere activity and proteins within a subdomain of the major human X chromosome array (PMID:12356743)
• Topoisomerase II-alpha expression in rectal epithelium has a significant circadian variation and giving topoisomerase II-targeted chemotherapeutic agents at the proper time of day might reduce their mucositis side effects. (PMID:12429798)
• Topo IIalpha may provide crucial information regarding selection of adenohypophyseal tumors responsive to antineoplastic therapy, such as invasive pituitary adenomas and pituitary carcinomas, which exhibit a high Topo IIalpha index. (PMID:12429800)
• promoter elements responsible for transcriptional inhibition of polo-like kinase 1 and topoisomerase IIalpha genes by p21(WAF1/CIP1/SDI1) (PMID:12429910)
• A heterodimer of this protein with only one ATP binding site can go through successive catalytic cycles (PMID:12480934)
• Phosphorylation of serine 1106 in the catalytic domain of this enzyme regulates enzymatic activity and drug sensitivity. (PMID:12569090)
• Thr792 in human TOP2 alpha is involved in enzyme catalysis (PMID:12646164)
• Analysis of TOP2A gene amplification and gene overexpression in newly diagnosed childhood ALL cases and inverse correlation with glucocorticoid resistance (PMID:12646941)
• induction of topoisomerase IIalpha expression by peroxisome proliferator-activated receptor gamma ligands via DR1-like site is an important mechanism for the enhancement of etoposide-induced apoptosis (PMID:12691917)
• topoisomerase II is actively exported from the nuclease and is mediated by a CRM1-dependent pathway (PMID:12821127)
• Results suggest that topo IIalpha-depleted cells with the droplet-like nuclear structure induce apoptosis, which is dependent on caspase and p53 activity during the G1 phase in mammalian cells. (PMID:12859955)
• data suggest that HER-2 amplifications are frequently linked to alterations of the TOP2A gene in bladder cancer (PMID:14566826)
• demonstrated that neither A or B isoform has any preference for a specific DNA conformation as substrate under the conditions used in these experiments (PMID:14596941)
• Amplification and deletion of topoisomerase IIalpha gene (TOP2A) is common in breast neoplasms and may account for both sensitivity and resistance to topoII-inhibitor-chemotherapy. (PMID:14632727)
• Topoisomerase IIalpha activity concentrates at heterochromatin during interphase and mitosis. (PMID:14978217)
• Topo-II alpha is a useful marker for diagnosing liposarcoma. (PMID:14989736)
• overexpression of topoisomerase (DNA) II alpha is associated with gastric cancer (PMID:14991576)
• Chromosomes were condensed and aligned at metaphase in topo IIalpha-knockdown cells. (PMID:14996935)
• alterations in the ATP binding domain of the enzyme are capable of altering the interactions of TOP2A with DNA (PMID:15037624)
• UVA-modified DNA is preferentially targeted and processed by topoisomerase IIalpha and IIbeta. (PMID:15044480)
• topo IIalpha destabilization depends on the newly identified domain, GRDD (glucose-regulated destruction domain), which was mapped to the N-terminal 70-170 amino acid sequence (PMID:15126503)
• 1,4-benzoquinone stimulated DNA cleavage by topoisomerase IIalpha in cultured human cells (PMID:15182198)
• review commentary on TOP2A as a proliferation marker, indicator of drug sensitivity, and prognostic factor in mantle cell lymphoma (PMID:15201855)
• Increased expression of DNA topoisomerase II alpha is associated with female breast cancer (PMID:15375522)
• topoIIalpha plays an essential catalytic role in chromosome segregation that cannot be complemented by topoIIbeta (PMID:15456904)
• Human topoisomerase II alpha appears to ligate the two scissile bonds of a DNA cleavage site in a nonconcerted fashion. (PMID:15491148)
• Cisplatin was shown to strongly inhibit the decatenation and relaxation activity of isolated human DNA topoisomerase IIalpha. (PMID:15602006)
• low-level amplification of TIIalpha gene locus may be sporadic mechanism of increased TIIalpha protein expression in pediatric non-brainstem glioma, which can coincide with low-level amplification of Her-2/neu (PMID:15809708)
• topo2a and HER-2 status might have therapeutic and prognostic implications. (PMID:15899781)
• We show that a R162K mutation in human topoisomerase II alpha renders this enzyme highly resistant towards vanadate while having little effect on bisdioxopiperazine sensitivity. (PMID:16053917)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	top2a	ENSDARG00000024488
mus_musculus	Top2a	ENSMUSG00000020914
rattus_norvegicus	Top2a	ENSRNOG00000053047

Paralogs (1): TOP2B (ENSG00000077097)

Protein

Protein identifiers

DNA topoisomerase 2-alpha — P11388 (reviewed: P11388)

Alternative names: DNA topoisomerase II, alpha isozyme

All UniProt accessions (3): P11388, J3KTB7, J3QR57

UniProt curated annotations — full annotation on UniProt →

Function. Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand. May play a role in regulating the period length of BMAL1 transcriptional oscillation.

Subunit / interactions. Homodimer. Interacts with COPS5. Interacts with RECQL5; this stimulates DNA decatenation. Interacts with SETMAR; stimulates the topoisomerase activity. Interacts with DHX9; this interaction occurs in a E2 enzyme UBE2I- and RNA-dependent manner, negatively regulates DHX9-mediated double-stranded DNA and RNA duplex helicase activity and stimulates TOP2A-mediated supercoiled DNA relaxation activity. Interacts with HNRNPU (via C-terminus); this interaction protects the topoisomerase TOP2A from degradation and positively regulates the relaxation of supercoiled DNA in a RNA-dependent manner. Interacts with MCM3AP isoform GANP. Interacts with ERCC6. Interacts with PLSCR1. Interacts with GCNA; this interaction allows the resolution of topoisomerase II (TOP2A) DNA-protein cross-links. Interacts with POL1RA/RPA1 (via dock II) and UBTF in the context of Pol I complex; may assist Pol I transcription initiation by releasing supercoils occurring during DNA unwinding. Interacts with TPRN; TPRN interacts with a number of DNA damage response proteins, is recruited to sites of DNA damage and may play a role in DNA damage repair. Interacts with FBXO28; this interaction leads to TOP2A proteasomal degradation.

Subcellular location. Cytoplasm. Nucleus. Nucleoplasm. Nucleolus.

Tissue specificity. Expressed in the tonsil, spleen, lymph node, thymus, skin, pancreas, testis, colon, kidney, liver, brain and lung. Also found in high-grade lymphomas, squamous cell lung tumors and seminomas.

Post-translational modifications. Phosphorylation has no effect on catalytic activity. However, phosphorylation at Ser-1106 by CSNK1D/CK1 promotes DNA cleavable complex formation. (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to stabilized SUMOylated TOP2A trapped in cleavage complexes, which halts the DNA damage response to TOP2A-induced double-strand DNA breaks. SUMOylated. Ubiquitinated in a FBXO28-dependent manner; leading to TOP2A proteasomal degradation.

Activity regulation. Specifically inhibited by the intercalating agent amsacrine.

Cofactor. Binds two Mg(2+) per subunit. The magnesium ions form salt bridges with both the protein and the DNA. Can also accept other divalent metal cations, such as Mn(2+) or Ca(2+).

Domain organisation. The N-terminus has several structural domains; the ATPase domain (about residues 1-265), the transducer domain (about 266-428) and the toprim domain (455-572). Comparing different structures shows ATP hydrolysis induces domain shifts in the N-terminus that are probably part of the mechanism of DNA cleavage and rejoining.

Miscellaneous. Eukaryotic topoisomerase I and II can relax both negative and positive supercoils, whereas prokaryotic enzymes relax only negative supercoils.

Similarity. Belongs to the type II topoisomerase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P11388-1	1	yes
P11388-2	2
P11388-3	3
P11388-4	4

RefSeq proteins (1): NP_001058* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001154	TopoII_euk	Family
IPR001241	Topo_IIA	Family
IPR002205	Topo_IIA_dom_A	Domain
IPR003594	HATPase_dom	Domain
IPR006171	TOPRIM_dom	Domain
IPR012542	DTHCT	Domain
IPR013506	Topo_IIA_bsu_dom2	Domain
IPR013757	Topo_IIA_A_a_sf	Homologous_superfamily
IPR013758	Topo_IIA_A/C_ab	Homologous_superfamily
IPR013759	Topo_IIA_B_C	Homologous_superfamily
IPR013760	Topo_IIA-like_dom_sf	Homologous_superfamily
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR018522	TopoIIA_CS	Conserved_site
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR031660	TOPRIM_C	Domain
IPR034157	TOPRIM_TopoII	Domain
IPR036890	HATPase_C_sf	Homologous_superfamily
IPR050634	DNA_Topoisomerase_II	Family

Pfam: PF00204, PF00521, PF01751, PF02518, PF08070, PF16898

Enzyme classification (BRENDA):

• EC 5.6.2.2 — DNA topoisomerase (ATP-hydrolysing) (BRENDA: 99 organisms, 409 substrates, 1698 inhibitors, 38 Km, 31 kcat entries)
• EC 5.99.1.3 — DNA topoisomerase (ATP-hydrolysing) (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0771–1.5	22
DNA	0.21–0.94	6
DATP	0.5–0.63	2
SUPERCOILED DNA	—	1

UniProt features (246 total): helix 52, strand 50, cross-link 45, modified residue 35, site 10, turn 9, binding site 9, mutagenesis site 7, sequence conflict 6, compositionally biased region 5, sequence variant 5, region of interest 5, splice variant 3, domain 2, chain 1, active site 1, short sequence motif 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
5NNE	X-RAY DIFFRACTION	1.15
9BQB	X-RAY DIFFRACTION	1.5
1ZXM	X-RAY DIFFRACTION	1.87
9BQ6	X-RAY DIFFRACTION	1.9
9BQ9	X-RAY DIFFRACTION	1.95
9BQ7	X-RAY DIFFRACTION	2.05
1ZXN	X-RAY DIFFRACTION	2.51
4R1F	X-RAY DIFFRACTION	2.51
8W50	X-RAY DIFFRACTION	2.67
4FM9	X-RAY DIFFRACTION	2.9
5GWK	X-RAY DIFFRACTION	3.15
6ZY5	ELECTRON MICROSCOPY	3.6
6ZY6	ELECTRON MICROSCOPY	4.1
6ZY7	ELECTRON MICROSCOPY	4.64
6ZY8	ELECTRON MICROSCOPY	7.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11388-F1	75.33	0.38

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 (11): 805 (o-(5’-phospho-dna)-tyrosine intermediate); 489 (interaction with dna); 492 (interaction with dna); 661 (interaction with dna); 662 (interaction with dna); 723 (interaction with dna); 757 (interaction with dna); 763 (interaction with dna); 804 (transition state stabilizer); 856 (important for dna bending; intercalates between base pairs of target dna); 931 (interaction with dna)

Ligand- & substrate-binding residues (9): 91; 120; 148–150; 161–168; 376–378; 461; 541; 541; 543

Post-translational modifications (80): 1259, 1276, 1283, 1286, 1363, 1367, 1373, 1385, 1422, 1442, 1454, 1459, 1484, 1492, 1, 4, 282, 1106, 1205, 1213 …

Mutagenesis-validated functional residues (7):

Position	Phenotype
342–344	reduced enzyme activity; abolishes stimulation of atpase activity upon dna binding.
342–344	strongly reduced enzyme activity; abolishes stimulation of atpase activity upon dna binding.
461	impairs bending of target dna. strongly reduced dna cleavage.
541	impairs bending of target dna. strongly reduced dna cleavage.
543	impairs bending of target dna. strongly reduced dna cleavage.
545	strongly reduced dna cleavage.
1469	abolishes binding to the antibody mpm2.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1362277	Transcription of E2F targets under negative control by DREAM complex
R-HSA-4615885	SUMOylation of DNA replication proteins

MSigDB gene sets: 596 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_CHROMOSOME_ORGANIZATION, KALMA_E2F1_TARGETS, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, MODULE_52, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GNF2_MSH2, HORIUCHI_WTAP_TARGETS_DN, MODULE_451, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, GNF2_CENPF

GO Biological Process (17): resolution of meiotic recombination intermediates (GO:0000712), sister chromatid segregation (GO:0000819), hematopoietic progenitor cell differentiation (GO:0002244), DNA topological change (GO:0006265), chromatin organization (GO:0006325), DNA damage response (GO:0006974), chromosome segregation (GO:0007059), female meiotic nuclear division (GO:0007143), apoptotic chromosome condensation (GO:0030263), embryonic cleavage (GO:0040016), regulation of circadian rhythm (GO:0042752), positive regulation of apoptotic process (GO:0043065), positive regulation of single stranded viral RNA replication via double stranded DNA intermediate (GO:0045870), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511), DNA metabolic process (GO:0006259), chromosome condensation (GO:0030261)

GO Molecular Function (17): magnesium ion binding (GO:0000287), DNA binding (GO:0003677), chromatin binding (GO:0003682), RNA binding (GO:0003723), DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity (GO:0003918), protein kinase C binding (GO:0005080), ATP binding (GO:0005524), ATP-dependent activity, acting on DNA (GO:0008094), DNA binding, bending (GO:0008301), protein homodimerization activity (GO:0042803), ubiquitin binding (GO:0043130), protein heterodimerization activity (GO:0046982), nucleotide binding (GO:0000166), DNA topoisomerase activity (GO:0003916), protein binding (GO:0005515), isomerase activity (GO:0016853), metal ion binding (GO:0046872)

GO Cellular Component (12): chromosome, centromeric region (GO:0000775), condensed chromosome (GO:0000793), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex (GO:0009330), protein-containing complex (GO:0032991), ribonucleoprotein complex (GO:1990904), nuclear chromosome (GO:0000228), centriole (GO:0005814)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
G0 and Early G1	1
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	3
chromosome organization	2
nucleic acid binding	2
binding	2
catalytic activity, acting on DNA	2
DNA binding	2
protein dimerization activity	2
chromosome	2
cellular anatomical structure	2
intracellular membraneless organelle	2
reciprocal meiotic recombination	1
meiosis I cell cycle process	1
nuclear chromosome segregation	1
hemopoiesis	1
cell differentiation	1
DNA metabolic process	1
DNA conformation change	1
cellular component organization	1
cellular response to stress	1
cell cycle process	1
female gamete generation	1
meiotic cell cycle	1
meiotic nuclear division	1
chromosome condensation	1
apoptotic nuclear changes	1
embryo development	1
cell division	1
circadian rhythm	1
regulation of biological process	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
single stranded viral RNA replication via double stranded DNA intermediate	1
positive regulation of viral genome replication	1
regulation of single stranded viral RNA replication via double stranded DNA intermediate	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
biological_process	1

Protein interactions and networks

STRING

6644 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOP2A	TOP1	P11387	960
TOP2A	CDK1	P06493	943
TOP2A	CCNB1	P14635	926
TOP2A	TOP3A	Q13472	914
TOP2A	TOP1MT	Q969P6	902
TOP2A	CCNA2	P20248	868
TOP2A	TDP2	O95551	865
TOP2A	MKI67	P46013	845
TOP2A	UBE2C	O00762	837
TOP2A	NEIL3	Q8TAT5	836
TOP2A	BIRC5	O15392	829
TOP2A	TYMS	P04818	813
TOP2A	CCNB2	O95067	809
TOP2A	CENPF	P49454	804
TOP2A	ASPM	Q8IZT6	804

IntAct

215 interactions, top by confidence:

A	B	Type	Score
CLOCK	BMAL1	psi-mi:“MI:0914”(association)	0.880
DDX21	HNRNPC	psi-mi:“MI:0915”(physical association)	0.750
MED25	MED24	psi-mi:“MI:0914”(association)	0.740
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
MED10	POLR2D	psi-mi:“MI:0914”(association)	0.640
PARP1	TOP2A	psi-mi:“MI:0914”(association)	0.600
CTNNB1	TOP2A	psi-mi:“MI:0914”(association)	0.570
TOP2A	CTNNB1	psi-mi:“MI:0403”(colocalization)	0.570
CTNNB1	TOP2A	psi-mi:“MI:0915”(physical association)	0.570
WAS	TOP1	psi-mi:“MI:0914”(association)	0.560
N	RBM47	psi-mi:“MI:0914”(association)	0.530
ULK3	AIP	psi-mi:“MI:0914”(association)	0.530
GRK7	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
MAP4K4	STRN	psi-mi:“MI:0914”(association)	0.530
MED27	POLR2D	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
HSD3B2	NARS1	psi-mi:“MI:0914”(association)	0.530
BRCA1	TOP2A	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (728): TOP2A (Affinity Capture-MS), TOP2A (Affinity Capture-MS), TOP2A (Affinity Capture-MS), TOP2A (Affinity Capture-MS), TOP2A (Reconstituted Complex), TOP2A (Affinity Capture-Western), TOP2A (Biochemical Activity), TOP2A (Biochemical Activity), TOP2A (Reconstituted Complex), TOP2A (Affinity Capture-MS), TOP2A (Affinity Capture-MS), TOP2A (Affinity Capture-MS), TOP2A (Reconstituted Complex), TOP2A (Affinity Capture-Western), TOP2A (Affinity Capture-RNA)

ESM2 similar proteins: A2XKU9, A4IHJ3, A7RHL5, A8E657, A9NK39, A9RBS1, B4YYA9, B5X8A5, F4JWP9, O16140, O42130, O42131, O46374, O80585, P11388, P11708, P14152, P15348, P23381, P41515, P41516, Q01320, Q02880, Q1JQD4, Q3T145, Q3ZBN0, Q498C5, Q498D9, Q558Y7, Q5R4J1, Q5ZME2, Q64399, Q64511, Q6AVK1, Q6DIY9, Q6PAB3, Q6TGV7, Q6V289, Q75HE6, Q7YRU4

Diamond homologs: A0A0G2Q9F8, A1SCM2, B8GXQ0, C1CVF4, C5C7X9, C5CHA8, G5ECQ8, O16140, O24308, O42130, O42131, O46374, O51859, O61078, O67137, O84192, O93794, P06786, P08096, P0A2I3, P0A2I4, P0AES4, P0AES5, P0AES6, P0AES7, P0AES8, P0CAX1, P11388, P12531, P13364, P14829, P15348, P22118, P22447, P27570, P29435, P30182, P30190, P34030, P34031

SIGNOR signaling

30 interactions.

A	Effect	B	Mechanism
PLK3	up-regulates	TOP2A	phosphorylation
PLK1	up-regulates	TOP2A	phosphorylation
CSNK2A1	up-regulates	TOP2A	phosphorylation
NFY	“up-regulates quantity by expression”	TOP2A	“transcriptional regulation”
TOP2A	up-regulates	Chromosome_segregation
TOP2A	down-regulates	Survival
PRKCB	“up-regulates activity”	TOP2A	phosphorylation
PRKCG	“up-regulates activity”	TOP2A	phosphorylation
CSNK2A1	unknown	TOP2A	phosphorylation
“2-(Decan-2-ylamino)ethyl 4-aminobenzoate”	“down-regulates activity”	TOP2A	“chemical inhibition”
4’-epidoxorubicin	“down-regulates activity”	TOP2A	“chemical inhibition”
“Daunorubicin hydrochloride”	“down-regulates activity”	TOP2A	“chemical inhibition”
“Doxorubicin hydrochloride”	“down-regulates activity”	TOP2A	“chemical inhibition”
etoposide	“down-regulates activity”	TOP2A	“chemical inhibition”
idarubicin	“down-regulates activity”	TOP2A	“chemical inhibition”
teniposide	“down-regulates activity”	TOP2A	“chemical inhibition”
valrubicin	“down-regulates activity”	TOP2A	“chemical inhibition”
doxorubicin	“down-regulates activity”	TOP2A	“chemical inhibition”
CSNK2A1	“down-regulates quantity by destabilization”	TOP2A	phosphorylation
GSK3B	“down-regulates quantity by destabilization”	TOP2A	phosphorylation
SCF-FBW7	“down-regulates quantity by destabilization”	TOP2A	polyubiquitination
CDK1	unknown	TOP2A	phosphorylation
YAP1	“up-regulates quantity by expression”	TOP2A	“transcriptional regulation”
YAP/TAZ	“up-regulates quantity by expression”	TOP2A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 243 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
HIV Transcription Elongation	6	12.0×	4e-04
mRNA Capping	5	11.3×	2e-03
Formation of HIV-1 elongation complex containing HIV-1 Tat	7	10.8×	3e-04
Tat-mediated elongation of the HIV-1 transcript	7	10.8×	3e-04
Formation of HIV elongation complex in the absence of HIV Tat	7	10.3×	3e-04
Formation of the Early Elongation Complex	5	10.0×	3e-03
Formation of the HIV-1 Early Elongation Complex	5	10.0×	3e-03
Signaling by ALK in cancer	6	9.7×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome disassembly	5	18.8×	1e-03
NLS-bearing protein import into nucleus	5	18.8×	1e-03
positive regulation of transcription elongation by RNA polymerase II	8	11.3×	2e-04
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	5	9.7×	1e-02
double-strand break repair	9	8.6×	3e-04
positive regulation of miRNA transcription	6	8.2×	7e-03
telomere maintenance	6	7.5×	1e-02
chromatin remodeling	19	6.5×	1e-07

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	102
Likely benign	18
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

3224 predictions. Top by Δscore:

Variant	Effect	Δscore
17:40389643:GATTT:G	acceptor_gain	1.0000
17:40389645:TTT:T	acceptor_gain	1.0000
17:40389646:TT:T	acceptor_gain	1.0000
17:40389648:C:CC	acceptor_gain	1.0000
17:40389648:C:CG	acceptor_loss	1.0000
17:40389960:CTCA:C	donor_loss	1.0000
17:40389961:TCAC:T	donor_loss	1.0000
17:40389962:CA:C	donor_loss	1.0000
17:40389963:A:AC	donor_gain	1.0000
17:40389963:AC:A	donor_gain	1.0000
17:40389964:C:CA	donor_loss	1.0000
17:40389964:C:CC	donor_gain	1.0000
17:40389964:CC:C	donor_gain	1.0000
17:40389964:CCTT:C	donor_gain	1.0000
17:40389964:CCTTG:C	donor_gain	1.0000
17:40390160:CTGAC:C	acceptor_gain	1.0000
17:40390161:TGACC:T	acceptor_loss	1.0000
17:40390164:CCTG:C	acceptor_loss	1.0000
17:40390165:CTG:C	acceptor_loss	1.0000
17:40391500:GCTTA:G	donor_loss	1.0000
17:40391501:CTTA:C	donor_loss	1.0000
17:40391502:TTACT:T	donor_loss	1.0000
17:40391503:TACTT:T	donor_loss	1.0000
17:40391504:A:AC	donor_gain	1.0000
17:40391505:C:CC	donor_gain	1.0000
17:40391505:CT:C	donor_gain	1.0000
17:40391505:CTT:C	donor_gain	1.0000
17:40391505:CTTT:C	donor_gain	1.0000
17:40391636:AAGGT:A	acceptor_gain	1.0000
17:40391637:AGGT:A	acceptor_gain	1.0000

AlphaMissense

10237 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:40399098:A:G	L1077P	1.000
17:40399906:A:C	F1054L	1.000
17:40399906:A:T	F1054L	1.000
17:40399907:A:G	F1054S	1.000
17:40399908:A:G	F1054L	1.000
17:40399910:C:G	R1053P	1.000
17:40400401:T:A	K936N	1.000
17:40400401:T:G	K936N	1.000
17:40400537:A:G	W931R	1.000
17:40400537:A:T	W931R	1.000
17:40400938:C:T	G859E	1.000
17:40400939:C:A	G859W	1.000
17:40400944:C:T	G857D	1.000
17:40400945:C:G	G857R	1.000
17:40400951:C:G	G855R	1.000
17:40400951:C:T	G855R	1.000
17:40401020:C:G	D832H	1.000
17:40402917:A:C	F807L	1.000
17:40402917:A:T	F807L	1.000
17:40402919:A:G	F807L	1.000
17:40402925:A:G	Y805H	1.000
17:40402932:A:C	S802R	1.000
17:40402932:A:T	S802R	1.000
17:40402934:T:G	S802R	1.000
17:40402936:G:T	A801D	1.000
17:40402951:C:T	G796D	1.000
17:40402966:C:A	G791V	1.000
17:40402966:C:T	G791D	1.000
17:40402967:C:G	G791R	1.000
17:40402968:A:C	F790L	1.000

dbSNP variants (sampled 300 via entrez): RS1000055132 (17:40397183 G>T), RS1000128067 (17:40397685 T>C), RS1000179563 (17:40388769 C>G,T), RS1000277681 (17:40390610 T>C), RS1000282291 (17:40393374 A>G,T), RS1000547976 (17:40408429 C>T), RS1000564615 (17:40395205 C>G), RS1000719072 (17:40418865 G>A), RS1000742699 (17:40388200 A>G), RS1000954443 (17:40413319 T>C), RS1001283103 (17:40415275 T>C), RS1001293222 (17:40407709 A>G,T), RS1001351029 (17:40417633 A>G), RS1001360256 (17:40405930 C>G), RS1001439637 (17:40415480 C>G,T)

Disease associations

OMIM: gene MIM:126430 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): long QT syndrome (MONDO:0002442)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004066_132	Hip circumference	4.000000e-08
GCST004066_19	Hip circumference	9.000000e-08
GCST004067_221	Hip circumference adjusted for BMI	3.000000e-07
GCST004067_29	Hip circumference adjusted for BMI	1.000000e-09
GCST90000025_584	Appendicular lean mass	4.000000e-10
GCST90002399_239	Neutrophil percentage of white cells	5.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1806 (SINGLE PROTEIN), CHEMBL2094255 (PROTEIN FAMILY), CHEMBL4106174 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,958,697 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1738	DEXRAZOXANE	4	34,186
CHEMBL178	DAUNORUBICIN	4	203,756
CHEMBL359744	DOXORUBICIN HYDROCHLORIDE	4	141,917
CHEMBL417	EPIRUBICIN	4	135,503
CHEMBL43	AMSACRINE	4	82,326
CHEMBL44657	ETOPOSIDE	4	226,069
CHEMBL53463	DOXORUBICIN	4	314,282
CHEMBL58	MITOXANTRONE	4	166,878
CHEMBL452231	TENIPOSIDE	4	136,487
CHEMBL8	CIPROFLOXACIN	4	97,708
CHEMBL84	TOPOTECAN	4	141,586
CHEMBL140	CURCUMIN	3	93,882
CHEMBL3317856	GEPOTIDACIN	3	215
CHEMBL1232279	NEMORUBICIN	2	15,656
CHEMBL203666	PIROXANTRONE	2	2,603
CHEMBL283120	AXL-1717	2	1,774
CHEMBL3039513	DECERNOTINIB	2	1,418
CHEMBL83520	LOSOXANTRONE	2	26,386

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
TOP2A EXPRESSION	Doxorubicin	Breast Cancer	Sensitivity/Response	CIViC B	EID909

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs181501757	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs181501757	TOP2A	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — DNA topoisomerases

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
etoposide	Inhibition	7.3	pIC50
myricetin	Inhibition	6.41	pIC50
doxorubicin	Inhibition	6.0	pIC50
mitoxantrone	Inhibition	5.28	pIC50

Binding affinities (BindingDB)

5 measured of 36 human assays (47 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL2259873	IC50	2100 nM
CHEMBL2260078	IC50	3400 nM
CHEMBL2260087	IC50	4000 nM
DI-O-ADAMANTOYLCURCUMIN	IC50	4500 nM
CHEMBL2260074	IC50	18000 nM

ChEMBL bioactivities

364 potent at pChembl≥5 of 740 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.68	IC50	0.21	nM	CHEMBL440125
8.82	IC50	1.5	nM	NEMORUBICIN
8.59	IC50	2.6	nM	IDARUBICIN
8.52	IC50	3	nM	EPIRUBICIN
8.31	IC50	4.9	nM	DOXORUBICIN
8.05	IC50	9	nM	CHEMBL47027
8.00	IC50	10	nM	DAUNORUBICIN
7.70	IC50	20	nM	CHEMBL108283
7.52	EC50	30	nM	CIPROFLOXACIN
7.35	IC50	45	nM	CHEMBL326664
7.27	IC50	54	nM	CHEMBL322325
7.27	Kd	54.1	nM	CHEMBL3752910
7.25	Kd	56.27	nM	CHEMBL5653589
7.25	ED50	56.25	nM	CHEMBL3752910
7.23	ED50	58.51	nM	CHEMBL5653589
7.22	IC50	60	nM	CHEMBL346068
7.20	IC50	63	nM	CHEMBL325543
7.19	Kd	64	nM	DECERNOTINIB
7.12	IC50	76	nM	CHEMBL2296491
7.02	EC50	96	nM	CHEMBL440642
7.01	EC50	98	nM	CHEMBL428339
6.94	IC50	116	nM	CHEMBL108404
6.90	IC50	125	nM	CHEMBL2296492
6.88	IC50	132	nM	CHEMBL2296490
6.82	IC50	150	nM	CHEMBL47885
6.80	EC50	160	nM	CHEMBL7877
6.80	EC50	160	nM	CHEMBL269139
6.70	IC50	200	nM	CHEMBL4463643
6.66	IC50	220	nM	CHEMBL47526
6.65	IC50	226	nM	CHEMBL325588
6.64	IC50	230	nM	CHEMBL4469453
6.62	IC50	240	nM	CHEMBL135778
6.48	EC50	330	nM	CHEMBL27233
6.48	EC50	330	nM	CHEMBL268458
6.46	IC50	350	nM	CHEMBL2260090
6.44	EC50	360	nM	CHEMBL7690
6.41	IC50	390	nM	MYRICETIN
6.40	IC50	400	nM	ACONITINE
6.38	IC50	420	nM	CHEMBL137098
6.36	IC50	440	nM	CHEMBL4470431
6.36	IC50	440	nM	CHEMBL337526
6.32	IC50	480	nM	TOPOTECAN
6.31	Kd	486	nM	AXL-1717
6.31	IC50	490	nM	CHEMBL335700
6.30	EC50	500	nM	CHEMBL132098
6.30	EC50	500	nM	CHEMBL121666
6.30	IC50	500	nM	CHEMBL173975
6.30	IC50	500	nM	CHEMBL367883
6.29	IC50	510	nM	CHEMBL101299
6.26	EC50	550	nM	CHEMBL30104

PubChem BioAssay actives

227 with measured affinity, of 6100 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
5-(3,4-dimethoxyphenyl)-6H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one	2037013: Inhibition of Topo IIalpha (unknown origin)	ic50	0.0002	uM
Idarubicin	2037013: Inhibition of Topo IIalpha (unknown origin)	ic50	0.0026	uM
Epirubicin	2037013: Inhibition of Topo IIalpha (unknown origin)	ic50	0.0030	uM
Doxorubicin	2037013: Inhibition of Topo IIalpha (unknown origin)	ic50	0.0049	uM
Daunorubicin	2037013: Inhibition of Topo IIalpha (unknown origin)	ic50	0.0100	uM
tert-butyl N-[3-(acridin-9-ylamino)-5-(methylcarbamoyloxymethyl)phenyl]carbamate	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	0.0200	uM
N-[3-(acridin-9-ylamino)-5-(hydroxymethyl)phenyl]methanesulfonamide	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	0.0450	uM
N-[3-(acridin-9-ylamino)-5-(hydroxymethyl)phenyl]-4-(dimethylamino)butanamide	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	0.0540	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149636: Binding affinity to human TOP2A incubated for 45 mins by Kinobead based pull down assay	kd	0.0541	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149636: Binding affinity to human TOP2A incubated for 45 mins by Kinobead based pull down assay	kd	0.0563	uM
18-[(3R)-3-aminopyrrolidin-1-yl]-19-fluoro-22-oxo-16-oxa-1-azahexacyclo[15.7.1.02,15.05,14.06,11.021,25]pentacosa-2(15),3,5(14),6,8,10,12,17(25),18,20,23-undecaene-23-carboxylic acid	437020: Induction of poison effect at DNA topoisomerase 2 by G-quadruplex interaction polymerase stop assay	ic50	0.0600	uM
[3-(acridin-9-ylamino)-5-(methanesulfonamido)phenyl]methyl acetate	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	0.0630	uM
[3-(acridin-9-ylamino)-5-aminophenyl]methyl N-methylcarbamate	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	0.1160	uM
N-[4-(1-benzofuran-2-yl)-8-hydroxyquinolin-7-yl]acetamide	1527439: Inhibition of human topoisomerase 2alpha mediated decatenation using kDNA as susbtrate preincubated for 20 mins followed by substrate and ATP addition and measured after 1 hr by ethidium bromide staining based gel electrophoresis method	ic50	0.2000	uM
3,4,5-trihydroxy-N-[3-[(3,4,5-trihydroxybenzoyl)amino]phenyl]benzamide	57230: Inhibitory concentration against relaxation activity of DNA topoisomerase II by detecting the conversion of supercoiled pBR322 DNA to its relaxed form	ic50	0.2200	uM
[3-(acridin-9-ylamino)phenyl]methanol	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	0.2260	uM
2-chloro-3-[(4-fluorophenyl)methoxy-thiophen-2-ylmethyl]quinoline	1600554: Inhibition of DNA topoisomerase 2 in human MCF7 cells incubated for 18 to 24 hrs by kinase assay	ic50	0.2300	uM
methyl N-[[14-[2-(diethylamino)ethyl]-4-hydroxy-8-thia-14,15-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-1(15),2(7),3,5,9,11,13(16)-heptaen-10-yl]methyl]carbamate	211289: In vitro evaluation for inhibitor of human topoisomerase II from HeLa cells.	ec50	0.3300	uM
[(1S,2R,3R,4R,5R,6S,7S,8R,9R,10R,13R,14R,16S,17S,18R)-8-acetyloxy-11-ethyl-5,7,14-trihydroxy-6,16,18-trimethoxy-13-(methoxymethyl)-11-azahexacyclo[7.7.2.12,5.01,10.03,8.013,17]nonadecan-4-yl] benzoate	2037013: Inhibition of Topo IIalpha (unknown origin)	ic50	0.4000	uM
14-[(3R)-3-aminopyrrolidin-1-yl]-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.04,9.017,21]henicosa-2,4,6,8,10,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.4200	uM
2-chloro-3-[(4-chlorophenyl)methoxy-thiophen-2-ylmethyl]quinoline	1600554: Inhibition of DNA topoisomerase 2 in human MCF7 cells incubated for 18 to 24 hrs by kinase assay	ic50	0.4400	uM
14-[(3S)-3-aminopyrrolidin-1-yl]-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.04,9.017,21]henicosa-2,4,6,8,10,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.4400	uM
14-[(3S)-3-aminopyrrolidin-1-yl]-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.05,10.017,21]henicosa-2(11),3,5,7,9,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.4900	uM
2-[4-[5-[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]furan-2-yl]phenyl]-1,4,5,6-tetrahydropyrimidine;dihydrochloride	57049: Inhibitory activity for 50% on topoisomerase II isolated from Giardia lamblia	ic50	0.5000	uM
N-[[1-[2-(diethylamino)ethylamino]-7-hydroxy-9-oxothioxanthen-4-yl]methyl]methanesulfonamide	211289: In vitro evaluation for inhibitor of human topoisomerase II from HeLa cells.	ec50	0.5000	uM
10-[(3S)-3-aminopyrrolidin-1-yl]-11-fluoro-14-oxo-8-oxa-1-azatetracyclo[7.7.1.02,7.013,17]heptadeca-2,4,6,9(17),10,12,15-heptaene-15-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.5100	uM
14-(3-aminopyrrolidin-1-yl)-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.05,10.017,21]henicosa-2(11),3,5,7,9,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.5500	uM
N-[[14-[2-(diethylamino)ethyl]-4-hydroxy-8-thia-14,15-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-1(15),2(7),3,5,9,11,13(16)-heptaen-10-yl]methyl]methanesulfonamide	211289: In vitro evaluation for inhibitor of human topoisomerase II from HeLa cells.	ec50	0.5500	uM
N-[4-(5-fluoro-2-hydroxyphenyl)-8-hydroxyquinolin-7-yl]-3-morpholin-4-ylpropanamide	1527439: Inhibition of human topoisomerase 2alpha mediated decatenation using kDNA as susbtrate preincubated for 20 mins followed by substrate and ATP addition and measured after 1 hr by ethidium bromide staining based gel electrophoresis method	ic50	0.6000	uM
15-fluoro-18-oxo-14-piperazin-1-yl-12-oxa-1-azapentacyclo[11.7.1.02,11.04,9.017,21]henicosa-2,4,6,8,10,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.6400	uM
N-[2-[[4-(2-aminoethylcarbamoyl)phenyl]methoxy]-4-carbamoylphenyl]-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide;dihydrochloride	1994665: Inhibition of human DNA topoisomerase 2 alpha assessed as relaxation of supercoiled plasmid pNO1 DNA incubated for 30 mins by fluorescence based analysis	ic50	0.6700	uM
N-[8-hydroxy-4-[4-(trifluoromethyl)phenyl]quinolin-7-yl]acetamide	1527439: Inhibition of human topoisomerase 2alpha mediated decatenation using kDNA as susbtrate preincubated for 20 mins followed by substrate and ATP addition and measured after 1 hr by ethidium bromide staining based gel electrophoresis method	ic50	0.7000	uM
18-[(3S)-3-aminopyrrolidin-1-yl]-19-fluoro-22-oxo-16-oxa-1-azahexacyclo[15.7.1.02,15.05,14.06,11.021,25]pentacosa-2(15),3,5(14),6,8,10,12,17(25),18,20,23-undecaene-23-carboxylic acid	437020: Induction of poison effect at DNA topoisomerase 2 by G-quadruplex interaction polymerase stop assay	ic50	0.7000	uM
N-[4-(acridin-9-ylamino)-3-methoxyphenyl]methanesulfonamide	211292: Tested for inhibition of topoisomerase II isolated from HeLa cells by DNA-cleavage assay	ec50	0.7200	uM
14-[(3S)-3-aminopyrrolidin-1-yl]-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.03,8.017,21]henicosa-2(11),3,5,7,9,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.7200	uM
6-N-tert-butyl-8-ethyl-2-N-[2-(2-morpholin-4-ylethoxy)quinolin-6-yl]-7H-purine-2,6-diamine	1994665: Inhibition of human DNA topoisomerase 2 alpha assessed as relaxation of supercoiled plasmid pNO1 DNA incubated for 30 mins by fluorescence based analysis	ic50	0.7300	uM
12-butan-2-yl-11-imino-9-(4-methoxyphenyl)-2-oxa-4,6,12,14-tetrazatricyclo[8.4.0.03,8]tetradeca-1(10),3(8),13-triene-5,7-dione	1939819: Inhibition of DNA topoisomerase 2 (unknown origin)	ic50	0.7520	uM
14-(3-aminopyrrolidin-1-yl)-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.03,8.017,21]henicosa-2(11),3,5,7,9,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.7700	uM
14-(3-aminopyrrolidin-1-yl)-15-fluoro-18-oxo-12-oxa-1-azapentacyclo[11.7.1.02,11.04,9.017,21]henicosa-2,4,6,8,10,13(21),14,16,19-nonaene-19-carboxylic acid	211295: Inhibition of topoisomerase II as conversion of catenated to decatenated KDNA	ic50	0.7700	uM
12-(2-hydroxyphenyl)-11-imino-9-(4-methoxyphenyl)-2-oxa-4,6,12,14-tetrazatricyclo[8.4.0.03,8]tetradeca-1(10),3(8),13-triene-5,7-dione	1939819: Inhibition of DNA topoisomerase 2 (unknown origin)	ic50	0.7760	uM
7-imino-9-(4-methoxyphenyl)-11,13-dioxo-N-phenyl-2-oxa-4,6,12,14-tetrazatricyclo[8.4.0.03,8]tetradeca-1(10),3(8),4-triene-6-carbothioamide	1939819: Inhibition of DNA topoisomerase 2 (unknown origin)	ic50	0.7910	uM
Etoposide	211292: Tested for inhibition of topoisomerase II isolated from HeLa cells by DNA-cleavage assay	ec50	0.8100	uM
2-(2,4,5,8,9,11-hexazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),3,5,7,9,12,14-heptaen-3-ylsulfanyl)-N-(3-methoxyphenyl)acetamide	1404822: Inhibition of human topoisomerase 2 using supercoiled pHOT1 DNA as substrate after 30 mins by agarose gel electrophoresis	ic50	0.8500	uM
6-amino-7-(1H-benzimidazol-2-yl)-5-[4-(dimethylamino)butyl]pyrrolo[2,3-b]pyrazine-2,3-dicarbonitrile	1274499: Inhibition of purified human topoisomerase 2-mediated relaxation of supercoiled pBR322 DNA at 50 uM incubated for 30 mins in presence of 1 mM ATP by agarose gel electrophoresis	ic50	0.9000	uM
N-(4-fluorophenyl)-2-(2,4,5,8,9,11-hexazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),3,5,7,9,12,14-heptaen-3-ylsulfanyl)acetamide	1404822: Inhibition of human topoisomerase 2 using supercoiled pHOT1 DNA as substrate after 30 mins by agarose gel electrophoresis	ic50	0.9400	uM
Doxorubicin Hydrochloride	1663790: Inhibition of human DNA topoisomerase 2 catalytic activity using supercoiled pRYG DNA as substrate measured after 45 mins in presence of ATP by agarose gel electrophoresis	ic50	0.9400	uM
5-amino-10-[(3S)-3-aminopyrrolidin-1-yl]-11-fluoro-14-oxo-8-oxa-1-azatetracyclo[7.7.1.02,7.013,17]heptadeca-2(7),3,5,9(17),10,12,15-heptaene-15-carboxylic acid	1459334: Inhibition of human topoisomerase-2alpha assessed as reduction in enzyme-mediated decatenation using kinetoplast DNA as substrate after 15 mins by ethidium bromide staining based agarose gel electrophoresis method	ic50	0.9700	uM
N-[4-(pyridin-2-ylsulfamoyl)phenyl]-2-([1,2,4]triazolo[4,3-a]quinoxalin-4-ylsulfanyl)acetamide	1942562: Inhibition of human Topoisomerase 2 incubated for 30 mins by ELISA assay	ic50	0.9700	uM
2,4,6-trimethyl-N-(4-oxo-2-phenylchromen-7-yl)benzenesulfonamide	1663790: Inhibition of human DNA topoisomerase 2 catalytic activity using supercoiled pRYG DNA as substrate measured after 45 mins in presence of ATP by agarose gel electrophoresis	ic50	0.9800	uM
[3-(acridin-9-ylamino)-5-(4-oxopentanoylamino)phenyl]methyl 4-oxopentanoate	57198: In vitro 50% inhibition of topoisomerase II mediated k-DNA decatenation	ic50	1.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Etoposide	decreases expression, decreases activity, increases phosphorylation, affects cotreatment, increases reaction (+8 more)	18
Doxorubicin	affects response to substance, affects cotreatment, affects binding, affects reaction, increases response to substance (+6 more)	16
quinone	affects binding, decreases activity, increases activity, increases expression, increases reaction (+1 more)	11
sodium arsenite	decreases expression, increases expression, affects expression	7
Amsacrine	affects response to substance, decreases expression, decreases response to substance, increases phosphorylation, increases response to substance (+1 more)	7
hydroquinone	affects cotreatment, increases reaction, affects activity, decreases activity	5
Fluorouracil	decreases expression, affects cotreatment, affects response to substance, affects reaction	5
bisphenol A	affects expression, decreases expression, increases expression	4
palbociclib	affects reaction, decreases expression, decreases reaction, increases expression	4
Adenosine Triphosphate	increases hydrolysis, decreases reaction	4
Cisplatin	decreases response to substance, affects expression, decreases expression, increases expression, increases response to substance (+1 more)	4
Estradiol	increases expression, increases response to substance	4
Tretinoin	increases expression, decreases expression	4
Resveratrol	decreases activity, decreases expression	3
Benzo(a)pyrene	decreases expression, increases expression	3
Curcumin	decreases expression, affects cotreatment	3
Progesterone	decreases expression, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
Cyclosporine	decreases expression	3
Aflatoxin B1	affects cotreatment, increases expression, decreases methylation, affects expression	3
alternariol	decreases activity	2
arsenite	affects binding, decreases reaction, increases expression	2
cobaltous chloride	decreases expression	2
alternariol monomethyl ether	decreases activity	2
xanthatin	decreases activity, decreases expression, increases expression	2
perfluorooctanoic acid	decreases expression	2
1,2-naphthoquinone	affects binding, decreases activity, affects activity	2
copper-thiosemicarbazone complex	affects activity, decreases reaction, increases hydrolysis, decreases activity	2
cannabidiol hydroxyquinone	decreases activity	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2

ChEMBL screening assays

1305 unique, capped per target: 1264 binding, 22 admet, 13 functional, 6 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003545	Binding	Inhibition of human topoisomerase 2alpha-mediated supercoiled pBR322 DNA relaxation at 5 ug/ml by agarose gel electrophoresis	Makaluvamine N: a new pyrroloiminoquinone from Zyzzya fuliginosa. — J Nat Prod
CHEMBL3271407	ADMET	Inhibition of human topoisomerase-2-alpha mediated double-stranded catenated kinetoplast DNA decatenation after 30 mins by agarose gel electrophoresis in presence of ATP	Haloemodin as novel antibacterial agent inhibiting DNA gyrase and bacterial topoisomerase I. — J Med Chem
CHEMBL5355516	Toxicity	Poison activity at human topoisomerase 2alpha using pBR322 DNA as substrate assessed as stabilization of enzyme-DNA cleavage complex by measuring linear DNA formation upto 200 uM incubated for 30 mins by EtBr staining based UV light analysi	Synthesis and evaluation of 7-(3-aminopropyloxy)-substituted flavone analogue as a topoisomerase IIα catalytic inhibitor and its sensitizing effect to enzalutamide in castration-resistant prostate cancer cells. — Eur J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0B24	NYH/187/162	Cancer cell line	Male
CVCL_0B25	NYH/187/165	Cancer cell line	Male
CVCL_IP18	HL-60/AMSA	Cancer cell line	Female
CVCL_IP19	KBM-3/AMSA	Cancer cell line	Female

Clinical trials (associated diseases)

66 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea