TOP3A

Summary

TOP3A (DNA topoisomerase III alpha, HGNC:11992) is a protein-coding gene on chromosome 17p11.2, encoding DNA topoisomerase 3-alpha (Q13472). Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. It is a common-essential gene (DepMap: required in 98.1% of cancer cell lines).

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 7156 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly, growth restriction, and increased sister chromatid exchange 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 493 total — 22 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 69
• Cancer dependency (DepMap): dependent in 98.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_004618

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11992
Approved symbol	TOP3A
Name	DNA topoisomerase III alpha
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	ZGRF7
Ensembl gene	ENSG00000177302
Ensembl biotype	protein_coding
OMIM	601243
Entrez	7156

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 8 protein_coding, 7 nonsense_mediated_decay, 6 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000321105, ENST00000461127, ENST00000469739, ENST00000472959, ENST00000477508, ENST00000489131, ENST00000493648, ENST00000580095, ENST00000580713, ENST00000581536, ENST00000582122, ENST00000582230, ENST00000582981, ENST00000583328, ENST00000583804, ENST00000584582, ENST00000584669, ENST00000584887, ENST00000585031, ENST00000924977, ENST00000924978, ENST00000924979, ENST00000924980, ENST00000947450

RefSeq mRNA: 2 — MANE Select: NM_004618 NM_001320759, NM_004618

CCDS: CCDS11194

Canonical transcript exons

ENST00000321105 — 19 exons

Exon	Start	End
ENSE00003485288	18308351	18308424
ENSE00003485911	18294703	18294785
ENSE00003493689	18306891	18306966
ENSE00003526652	18302264	18302434
ENSE00003527999	18305112	18305220
ENSE00003531379	18282698	18282841
ENSE00003535546	18277675	18278357
ENSE00003561752	18271428	18274980
ENSE00003563505	18280536	18280658
ENSE00003601220	18290842	18291027
ENSE00003610275	18290557	18290686
ENSE00003613599	18302580	18302723
ENSE00003619636	18292645	18292852
ENSE00003629337	18285407	18285520
ENSE00003636508	18285142	18285307
ENSE00003681199	18299559	18299633
ENSE00003685088	18301885	18301985
ENSE00003734992	18308882	18308941
ENSE00003844694	18314599	18314994

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 89.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6977 / max 203.1126, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164825	14.5632	1802
164824	3.1345	1323

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	89.21	gold quality
ganglionic eminence	UBERON:0004023	88.93	gold quality
ventricular zone	UBERON:0003053	88.64	gold quality
bone marrow cell	CL:0002092	87.78	gold quality
monocyte	CL:0000576	86.51	gold quality
leukocyte	CL:0000738	86.44	gold quality
bone marrow	UBERON:0002371	86.42	gold quality
cortical plate	UBERON:0005343	85.52	gold quality
adrenal tissue	UBERON:0018303	85.38	gold quality
stromal cell of endometrium	CL:0002255	84.86	gold quality
granulocyte	CL:0000094	84.45	gold quality
tonsil	UBERON:0002372	83.80	gold quality
colonic epithelium	UBERON:0000397	83.48	gold quality
endometrium	UBERON:0001295	83.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.95	gold quality
cerebellum	UBERON:0002037	82.68	gold quality
cerebellar cortex	UBERON:0002129	82.65	gold quality
cerebellar hemisphere	UBERON:0002245	82.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.21	gold quality
muscle tissue	UBERON:0002385	82.02	gold quality
skeletal muscle tissue	UBERON:0001134	81.86	gold quality
lymph node	UBERON:0000029	81.77	gold quality
calcaneal tendon	UBERON:0003701	81.77	gold quality
liver	UBERON:0002107	81.63	gold quality
superior frontal gyrus	UBERON:0002661	81.56	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.51	gold quality
urinary bladder	UBERON:0001255	81.42	gold quality
prefrontal cortex	UBERON:0000451	81.34	gold quality
vermiform appendix	UBERON:0001154	81.17	gold quality
placenta	UBERON:0001987	80.95	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, EGR2, FOS, JUN, SP1, USF1, USF2, YY1

miRNA regulators (miRDB)

95 targeting TOP3A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 25)

• Dual localization to mitochondria and nucleus (PMID:12209014)
• The Bloom’s syndrome helicase stimulates the activity of topoisomerase IIIalpha (PMID:12433984)
• The effects of TOP3 on telomere binding in human and S. cerevisiae cells are reported. (PMID:16546998)
• BLM, Topo IIIalpha, and BLAP75 constitute a dissolvasome complex that processes HR intermediates to limit DNA crossover formation (PMID:16595695)
• BLM is stably associated with TOP3A. (PMID:17728255)
• evolutionarily conserved N-terminal third of BLAP75 mediates complex formation with BLM and Topo IIIalpha and that the DNA binding activity resides in the C-terminal third of this novel protein. (PMID:18390547)
• Topo IIIalpha is an important telomere-associated factor, essential for telomere maintenance and chromosome stability in ALT cells, and speculate on its potential mechanistic function. (PMID:18418389)
• Individuals carrying genetic variants of the BLM-TOP3A-RMI1 complex have an increased risk of acute myeloid leukemia/myelodysplatic syndromes, malignant melanoma, bladder and breast cancer. (PMID:19432957)
• G-quadruplex ligand telomestatin impairs binding of topoisomerase IIIalpha to G-quadruplex-forming oligonucleotides and uncaps telomeres in ALT cells (PMID:19742304)
• human topoisomerase IIIalpha functions as a decatenase with the assistance of BLM and RMI1 to facilitate the processing of homologous recombination intermediates without crossing over as a mechanism to preserve genome integrity (PMID:20445207)
• TOP3A, a new partner gene fused to MLL in an adult patient with de novo acute myeloid leukaemia. (PMID:22050635)
• Study found a correlation between topoisomerase IIIalpha immunoexpression and oral squamous cell carcinoma (OSCC) cancer stem cell immunophenotypes. However, results did not show a prognostic significance of topoisomerases in OSCC> (PMID:22672768)
• MPS1 protein-dependent phosphorylation of RecQ-mediated genome instability protein 2 (RMI2) at serine 112 is essential for BLM-Topo III alpha-RMI1-RMI2 (BTR) protein complex function upon spindle assembly checkpoint (SAC) activation during mitosis (PMID:24108125)
• hTOP3alpha interacts with p53, regulates p53 and p21 expression, and contributes to the p53-mediated tumor suppression (PMID:24526736)
• The results show that Topo IIIalpha stimulates DNA unwinding by BLM in a manner that is potentiated by RMI1-RMI2, and that the processivity of resection is reliant on the Topo IIIalpha-RMI1-RMI2 complex. (PMID:25200081)
• Top3alpha is shown to be an essential component of the mitochondrial DNA replication machinery and as the first component of the mitochondrial DNA separation machinery. (PMID:29290614)
• Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells. (PMID:31846834)
• Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder. (PMID:33631320)
• Prediction of recurrence from metabolites and expression of TOP2A and EZH2 in prostate cancer patients treated with radiotherapy. (PMID:35032074)
• Duplex DNA and BLM regulate gate opening by the human TopoIIIalpha-RMI1-RMI2 complex. (PMID:35102151)
• The toposiomerase IIIalpha-RMI1-RMI2 complex orients human Bloom’s syndrome helicase for efficient disruption of D-loops. (PMID:35115525)
• TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT. (PMID:35920001)
• Two type I topoisomerases maintain DNA topology in human mitochondria. (PMID:36215039)
• The MRN complex and topoisomerase IIIa-RMI1/2 synchronize DNA resection motor proteins. (PMID:36529288)
• Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability. (PMID:37013609)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	top3a	ENSDARG00000052827
mus_musculus	Top3a	ENSMUSG00000002814
rattus_norvegicus	Top3a	ENSRNOG00000005099
drosophila_melanogaster	Top3alpha	FBGN0040268
caenorhabditis_elegans		WBGENE00006596

Paralogs (1): TOP3B (ENSG00000100038)

Protein

Protein identifiers

DNA topoisomerase 3-alpha — Q13472 (reviewed: Q13472)

Alternative names: DNA topoisomerase III alpha

All UniProt accessions (9): J3KRR9, J3KS96, J3QR18, J3QS25, K7EJ41, K7EL07, K7ELI7, K7EMT6, Q13472

UniProt curated annotations — full annotation on UniProt →

Function. Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5’-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3’-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 3’-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone. As an essential component of the RMI complex it is involved in chromosome separation and the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Has DNA decatenation activity. It is required for mtDNA decatenation and segregation after completion of replication, in a process that does not require BLM, RMI1 and RMI2.

Subunit / interactions. Binds ssDNA. Interacts (via N-terminal region) with BLM; the interaction is direct. Directly interacts with RMI1. Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM.

Subcellular location. Mitochondrion matrix.

Tissue specificity. High expression is found in testis, heart, skeletal muscle and pancreas.

Disease relevance. Microcephaly, growth restriction, and increased sister chromatid exchange 2 (MGRISCE2) [MIM:618097] An autosomal recessive disorder characterized by intrauterine growth restriction, poor postnatal growth with short stature and microcephaly, and increased sister chromatid exchange on cell studies. The disease is caused by variants affecting the gene represented in this entry. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 (PEOB5) [MIM:618098] A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. PEOB5 features include slowly progressive ptosis, intermittent double vision, cardiac arrhythmias, exercise intolerance, proximal limb and neck muscle weakness, and cerebellar ataxia. Patients skeletal muscle biopsy show numerous COX-deficient ragged-red fibers, increased mtDNA deletions, and extensive variable mtDNA rearrangements. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the type IA topoisomerase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13472-1	Long	yes
Q13472-2	Short
Q13472-3	3

RefSeq proteins (2): NP_001307688, NP_004609* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000380	Topo_IA	Family
IPR003601	Topo_IA_2	Domain
IPR003602	Topo_IA_DNA-bd_dom	Domain
IPR006171	TOPRIM_dom	Domain
IPR010666	Znf_GRF	Domain
IPR013497	Topo_IA_cen	Domain
IPR013498	Topo_IA_Znf	Domain
IPR013824	Topo_IA_cen_sub1	Homologous_superfamily
IPR013825	Topo_IA_cen_sub2	Homologous_superfamily
IPR013826	Topo_IA_cen_sub3	Homologous_superfamily
IPR023405	Topo_IA_core_domain	Homologous_superfamily
IPR023406	Topo_IA_AS	Active_site
IPR034144	TOPRIM_TopoIII	Domain

Pfam: PF01131, PF01396, PF01751, PF06839

UniProt features (74 total): helix 25, strand 16, binding site 8, sequence variant 7, zinc finger region 3, turn 3, region of interest 3, domain 2, compositionally biased region 2, splice variant 2, chain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4CGY	X-RAY DIFFRACTION	2.85
4CHT	X-RAY DIFFRACTION	3.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13472-F1	84.14	0.62

Functional residue map

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

Catalytic / active sites (1): 362 (o-(5’-phospho-dna)-tyrosine intermediate)

Ligand- & substrate-binding residues (8): 813; 815; 838; 843; 897; 899; 922; 930

Mutagenesis-validated functional residues (1):

Position	Phenotype
362	decreased dna decatenation.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-912446	Meiotic recombination
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709570	Impaired BRCA2 binding to RAD51
R-HSA-9709603	Impaired BRCA2 binding to PALB2
R-HSA-9913635	Strand-asynchronous mitochondrial DNA replication

MSigDB gene sets: 305 (showing top): PID_FANCONI_PATHWAY, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, RRAGTTGT_UNKNOWN, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_CHROMOSOME_SEPARATION, KAUFFMANN_DNA_REPAIR_GENES, KEGG_HOMOLOGOUS_RECOMBINATION, YY1_Q6, AACWWCAANK_UNKNOWN, GOBP_DNA_CONFORMATION_CHANGE

GO Biological Process (8): double-strand break repair via homologous recombination (GO:0000724), DNA topological change (GO:0006265), DNA repair (GO:0006281), DNA recombination (GO:0006310), mitochondrial DNA metabolic process (GO:0032042), chromosome separation (GO:0051304), meiotic cell cycle (GO:0051321), resolution of DNA recombination intermediates (GO:0071139)

GO Molecular Function (9): DNA binding (GO:0003677), single-stranded DNA binding (GO:0003697), DNA topoisomerase type I (single strand cut, ATP-independent) activity (GO:0003917), zinc ion binding (GO:0008270), nucleic acid binding (GO:0003676), DNA topoisomerase activity (GO:0003916), protein binding (GO:0005515), isomerase activity (GO:0016853), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), PML body (GO:0016605), RecQ family helicase-topoisomerase III complex (GO:0031422), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
Resolution of D-Loop Structures	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2
HDR through Homologous Recombination (HRR)	1
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
G2/M Checkpoints	1
Meiosis	1
Diseases of DNA Double-Strand Break Repair	1
DNA Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	5
mitochondrion	2
DNA binding	2
binding	2
intracellular membrane-bounded organelle	2
recombinational repair	1
double-strand break repair	1
DNA conformation change	1
DNA damage response	1
chromosome segregation	1
cell cycle process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
DNA recombination	1
nucleic acid binding	1
DNA topoisomerase activity	1
transition metal ion binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on DNA	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular organelle lumen	1
nuclear body	1
chromosome	1
DNA helicase complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOP3A	RMI2	Q96E14	999
TOP3A	RMI1	Q9H9A7	999
TOP3A	DNA2	P51530	995
TOP3A	FANCM	Q8IYD8	955
TOP3A	BLM	P54132	952
TOP3A	WRN	Q14191	928
TOP3A	TOP2A	P11388	914
TOP3A	RAD51	Q06609	884
TOP3A	EXO1	Q9UQ84	877
TOP3A	TOP1MT	Q969P6	847
TOP3A	FANCE	Q9HB96	842
TOP3A	MUS81	Q96NY9	842
TOP3A	RECQL	P46063	842
TOP3A	RECQL5	O94762	835
TOP3A	FANCF	Q9NPI8	833

IntAct

97 interactions, top by confidence:

A	B	Type	Score
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
TOP3A	RMI1	psi-mi:“MI:0407”(direct interaction)	0.940
RMI1	TOP3A	psi-mi:“MI:0914”(association)	0.940
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
RMI1	BLM	psi-mi:“MI:0914”(association)	0.930
BLM	TOP3A	psi-mi:“MI:0914”(association)	0.890
TOP3A	BLM	psi-mi:“MI:0915”(physical association)	0.890
BLM	TOP3A	psi-mi:“MI:0403”(colocalization)	0.890
RMI2	BLM	psi-mi:“MI:0914”(association)	0.830
ERCC6L	PLK1	psi-mi:“MI:0914”(association)	0.790
RIF1	BLM	psi-mi:“MI:0914”(association)	0.740
SPIDR	BLM	psi-mi:“MI:0914”(association)	0.660
BLM	RPA2	psi-mi:“MI:0914”(association)	0.640
RIF1	RPA2	psi-mi:“MI:0914”(association)	0.550
RMI2	BLM	psi-mi:“MI:0914”(association)	0.530
MECP2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530

BioGRID (188): RMI1 (Co-crystal Structure), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Co-fractionation), TOP3A (Co-fractionation), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TOP3A (Affinity Capture-MS), TSNAX (Two-hybrid)

ESM2 similar proteins: A0A0L0P6P7, A4I2L4, A5PKR8, A8D8P8, A9U328, A9VB27, A9ZSZ2, D3TQJ5, F4IE66, F4ISQ7, O22899, O43143, O54747, O60126, O61660, O70157, O76922, O95985, O96651, P13099, P54358, P90829, P97283, Q07803, Q08BB1, Q0J0S6, Q13472, Q20875, Q22307, Q23223, Q4P1V1, Q5R9V1, Q5RAZ4, Q5RBD4, Q5XQC7, Q7K3M5, Q80VY9, Q8K0D5, Q8T2T7, Q96RP9

Diamond homologs: A0A0L0P6P7, C7J0A2, F4ISQ7, O60126, O61660, O70157, O73954, O95985, O96651, P13099, Q0J0S6, Q13472, Q8T2T7, Q9LVP1, Q9NG98, Q9Z321, O28469, Q9YB01, Q0VGT4, Q5HZL1, Q68G58, Q6DDT4, Q86YA3, Q8K203, Q8TAT5, Q9UBZ4, A0A1L8HU22, B6SFA4, F1RCY6, O74939, O76512, O94387, P23249, P30771, Q00416, Q09449, Q09820, Q1LXK5, Q3MHN7, Q54I89

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 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
Resolution of D-Loop Structures	6	53.6×	5e-08
Removal of the Flap Intermediate from the C-strand	5	44.7×	2e-06
Impaired BRCA2 binding to RAD51	8	34.8×	1e-08
HDR through Single Strand Annealing (SSA)	8	33.0×	1e-08
Impaired BRCA2 binding to PALB2	5	32.2×	1e-05
Presynaptic phase of homologous DNA pairing and strand exchange	8	30.6×	1e-08
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	5	29.8×	1e-05
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	5	29.8×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of double-strand break repair via homologous recombination	5	33.6×	5e-05
base-excision repair	6	30.2×	9e-06
nucleotide-excision repair	6	24.7×	2e-05
telomere maintenance	6	17.3×	1e-04
proton motive force-driven mitochondrial ATP synthesis	6	17.0×	1e-04
aerobic respiration	6	16.0×	2e-04
double-strand break repair via homologous recombination	9	15.1×	3e-06
double-strand break repair	5	10.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	13
Uncertain significance	195
Likely benign	197
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1955432	NM_004618.5(TOP3A):c.1497dup (p.Phe500fs)	Pathogenic
2121541	NM_004618.5(TOP3A):c.2054_2055del (p.Cys685fs)	Pathogenic
2716366	NM_004618.5(TOP3A):c.1120_1121del (p.Leu374fs)	Pathogenic
2811047	NM_004618.5(TOP3A):c.922dup (p.Met308fs)	Pathogenic
2873635	NM_004618.5(TOP3A):c.1294C>T (p.Arg432Ter)	Pathogenic
2887680	NM_004618.5(TOP3A):c.1171dup (p.Ala391fs)	Pathogenic
3028909	NM_004618.5(TOP3A):c.614A>G (p.Asp205Gly)	Pathogenic
3243159	NC_000017.10:g.(?18193851)(18208554_?)del	Pathogenic
3377253	NM_004618.5(TOP3A):c.1111delinsGG (p.Pro371fs)	Pathogenic
3682719	NM_004618.5(TOP3A):c.2544G>A (p.Trp848Ter)	Pathogenic
3714403	NM_004618.5(TOP3A):c.796del (p.Ile266fs)	Pathogenic
4281651	NM_004618.5(TOP3A):c.990+1G>A	Pathogenic
446285	NM_004618.5(TOP3A):c.298A>G (p.Met100Val)	Pathogenic
446286	NM_004618.5(TOP3A):c.403C>T (p.Arg135Ter)	Pathogenic
4695013	NM_004618.5(TOP3A):c.307C>T (p.Arg103Ter)	Pathogenic
4716914	NM_004618.5(TOP3A):c.2269_2323del (p.Pro757fs)	Pathogenic
4728452	NM_004618.5(TOP3A):c.2499del (p.Gln834fs)	Pathogenic
4738857	NM_004618.5(TOP3A):c.1349del (p.Gln450fs)	Pathogenic
4770028	NM_004618.5(TOP3A):c.523C>T (p.Arg175Ter)	Pathogenic
4799989	NM_004618.5(TOP3A):c.1349_1350del (p.Gln450fs)	Pathogenic
560203	NM_004618.5(TOP3A):c.2271dup (p.Arg758fs)	Pathogenic
560204	NM_004618.5(TOP3A):c.2428del (p.Ser810fs)	Pathogenic
1013128	NM_004618.5(TOP3A):c.1155del (p.Asp386fs)	Likely pathogenic
1694834	NM_004618.5(TOP3A):c.991-1G>A	Likely pathogenic
1707336	NM_004618.5(TOP3A):c.990+1G>T	Likely pathogenic
1976108	NM_004618.5(TOP3A):c.314+1G>A	Likely pathogenic
2129441	NM_004618.5(TOP3A):c.815-2A>G	Likely pathogenic
2814255	NM_004618.5(TOP3A):c.391-1G>A	Likely pathogenic
2872409	NM_004618.5(TOP3A):c.644-11_644-2del	Likely pathogenic
3063833	NC_000017.10:g.(18210281_18211664)_(18212256_18217912)dup	Likely pathogenic

SpliceAI

2872 predictions. Top by Δscore:

Variant	Effect	Δscore
17:18274978:TCCC:T	acceptor_loss	1.0000
17:18274979:CC:C	acceptor_gain	1.0000
17:18274980:CC:C	acceptor_gain	1.0000
17:18274980:CCTG:C	acceptor_loss	1.0000
17:18274981:CTGTC:C	acceptor_loss	1.0000
17:18274982:T:C	acceptor_loss	1.0000
17:18282695:CA:C	donor_loss	1.0000
17:18282696:A:AC	donor_gain	1.0000
17:18282696:AC:A	donor_gain	1.0000
17:18282696:ACCCG:A	donor_gain	1.0000
17:18282697:C:CC	donor_gain	1.0000
17:18282697:C:CG	donor_loss	1.0000
17:18282697:CC:C	donor_gain	1.0000
17:18282697:CCCG:C	donor_gain	1.0000
17:18282697:CCCGC:C	donor_gain	1.0000
17:18282750:T:TA	donor_gain	1.0000
17:18282837:CCAAT:C	acceptor_gain	1.0000
17:18282838:CAAT:C	acceptor_gain	1.0000
17:18282838:CAATC:C	acceptor_gain	1.0000
17:18282839:AAT:A	acceptor_gain	1.0000
17:18282839:AATC:A	acceptor_loss	1.0000
17:18282840:AT:A	acceptor_gain	1.0000
17:18282841:TC:T	acceptor_loss	1.0000
17:18282842:C:CC	acceptor_gain	1.0000
17:18282842:CTGAA:C	acceptor_loss	1.0000
17:18285138:TTA:T	donor_loss	1.0000
17:18285139:TACTT:T	donor_loss	1.0000
17:18285140:A:AC	donor_gain	1.0000
17:18285140:ACTT:A	donor_gain	1.0000
17:18285141:C:CG	donor_gain	1.0000

AlphaMissense

6588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:18285244:A:G	L592P	1.000
17:18285511:G:T	A536D	1.000
17:18290573:C:A	M527I	1.000
17:18290573:C:G	M527I	1.000
17:18290573:C:T	M527I	1.000
17:18290586:A:G	L523P	1.000
17:18302434:C:T	G215E	1.000
17:18302588:A:G	L212P	1.000
17:18302594:A:G	L210P	1.000
17:18302603:C:A	R207M	1.000
17:18306966:C:A	W105C	1.000
17:18306966:C:G	W105C	1.000
17:18314654:T:A	K42I	1.000
17:18285256:A:G	L588P	0.999
17:18285407:C:G	G571R	0.999
17:18285415:A:G	L568P	0.999
17:18285424:C:T	G565D	0.999
17:18285425:C:G	G565R	0.999
17:18285475:C:G	R548P	0.999
17:18285512:C:G	A536P	0.999
17:18285515:C:G	D535H	0.999
17:18285520:C:T	G533D	0.999
17:18290557:C:G	G533R	0.999
17:18290574:A:C	M527R	0.999
17:18290574:A:G	M527T	0.999
17:18290574:A:T	M527K	0.999
17:18290586:A:T	L523H	0.999
17:18292684:G:C	H414Q	0.999
17:18292684:G:T	H414Q	0.999
17:18292686:G:C	H414D	0.999

dbSNP variants (sampled 300 via entrez): RS1000125969 (17:18311524 C>T), RS1000176296 (17:18315742 G>A), RS1000289068 (17:18301633 T>C), RS1000299292 (17:18276141 G>T), RS1000349437 (17:18305567 G>A), RS1000352960 (17:18292189 C>G), RS1000657514 (17:18301362 T>G), RS1000736344 (17:18274275 G>A,C), RS1000767340 (17:18294949 C>A), RS1000785472 (17:18274588 G>A,C), RS1000798703 (17:18295357 T>A,G), RS1000801038 (17:18293139 C>T), RS1000839618 (17:18316872 T>A,C), RS1000857729 (17:18300879 G>C,T), RS1000936531 (17:18293516 A>G)

Disease associations

OMIM: gene MIM:601243 | disease phenotypes: MIM:618098, MIM:618097

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly, growth restriction, and increased sister chromatid exchange 2	Definitive	Autosomal recessive
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5	Strong	Autosomal recessive

Mondo (4): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 (MONDO:0020845), microcephaly, growth restriction, and increased sister chromatid exchange 2 (MONDO:0020628), mitochondrial disease (MONDO:0044970), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (1): Mitochondrial disease (Orphanet:68380)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000479	Abnormal retinal morphology
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000590	Progressive external ophthalmoplegia
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0000716	Depression
HP:0000763	Sensory neuropathy
HP:0000957	Cafe-au-lait spot
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001511	Intrauterine growth retardation
HP:0001621	Weak voice
HP:0001638	Cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002067	Bradykinesia
HP:0002136	Broad-based gait
HP:0002345	Action tremor

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006624_112	Systolic blood pressure	2.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ozone	affects cotreatment, increases expression, increases abundance	3
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
beta-methylcholine	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
monomethylarsonous acid	increases expression	1
torcetrapib	increases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Adenine	decreases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Colchicine	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Etoposide	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	affects expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy