TOPBP1

Summary

TOPBP1 (DNA topoisomerase II binding protein 1, HGNC:17008) is a protein-coding gene on chromosome 3q22.1, encoding DNA topoisomerase 2-binding protein 1 (Q92547). Scaffold protein that acts as a key protein-protein adapter in DNA replication and DNA repair. It is a common-essential gene (DepMap: required in 99.1% of cancer cell lines).

This gene encodes a binding protein which interacts with the C-terminal region of topoisomerase II beta. This interaction suggests a supportive role for this protein in the catalytic reactions of topoisomerase II beta through transient breakages of DNA strands.

Source: NCBI Gene 11073 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (No Known Disease Relationship, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 258 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_007027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17008
Approved symbol	TOPBP1
Name	DNA topoisomerase II binding protein 1
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0259, TOP2BP1, Dpb11
Ensembl gene	ENSG00000163781
Ensembl biotype	protein_coding
OMIM	607760
Entrez	11073

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000260810, ENST00000503338, ENST00000503464, ENST00000505804, ENST00000506779, ENST00000509162, ENST00000511439, ENST00000513818, ENST00000572787, ENST00000642236, ENST00000881661, ENST00000881662, ENST00000881663, ENST00000933451, ENST00000933452, ENST00000953681

RefSeq mRNA: 2 — MANE Select: NM_007027 NM_001363889, NM_007027

CCDS: CCDS46919, CCDS87136

Canonical transcript exons

ENST00000260810 — 28 exons

Exon	Start	End
ENSE00000933924	133661044	133661134
ENSE00000933926	133657798	133657941
ENSE00000933927	133656676	133656857
ENSE00000933934	133643200	133643372
ENSE00000933939	133628362	133628471
ENSE00000933945	133617160	133617326
ENSE00000933946	133616814	133616925
ENSE00000933947	133612389	133612552
ENSE00000933948	133611004	133611141
ENSE00000933949	133608873	133608962
ENSE00001018318	133659016	133659150
ENSE00001078161	133644020	133644363
ENSE00001078166	133639959	133640170
ENSE00001150552	133628560	133628733
ENSE00001150558	133637876	133638162
ENSE00001289360	133652463	133652629
ENSE00001289455	133600238	133601393
ENSE00001289464	133661769	133661941
ENSE00001289481	133618213	133618433
ENSE00003474574	133649780	133649943
ENSE00003502982	133655290	133655486
ENSE00003510871	133623091	133623193
ENSE00003517080	133608535	133608696
ENSE00003523343	133649383	133649633
ENSE00003615031	133620155	133620347
ENSE00003615376	133623311	133623457
ENSE00003657183	133624052	133624175
ENSE00003672276	133653345	133653524

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 94.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.6935 / max 172.5028, expressed in 1789 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44658	17.9961	1782
44657	1.3773	600
44656	0.3201	191

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	94.86	gold quality
ventricular zone	UBERON:0003053	93.72	gold quality
ganglionic eminence	UBERON:0004023	92.74	gold quality
male germ cell	CL:0000015	91.86	gold quality
bone marrow	UBERON:0002371	91.70	gold quality
cortical plate	UBERON:0005343	90.85	gold quality
bone marrow cell	CL:0002092	90.56	gold quality
rectum	UBERON:0001052	90.26	gold quality
calcaneal tendon	UBERON:0003701	90.07	gold quality
vermiform appendix	UBERON:0001154	89.65	gold quality
monocyte	CL:0000576	89.54	gold quality
mononuclear cell	CL:0000842	89.44	gold quality
lymph node	UBERON:0000029	89.43	gold quality
embryo	UBERON:0000922	89.38	gold quality
leukocyte	CL:0000738	89.21	gold quality
body of pancreas	UBERON:0001150	88.70	gold quality
adrenal tissue	UBERON:0018303	88.66	gold quality
granulocyte	CL:0000094	88.61	gold quality
tibia	UBERON:0000979	88.44	gold quality
skin of hip	UBERON:0001554	88.42	gold quality
epithelium of nasopharynx	UBERON:0001951	88.15	gold quality
tonsil	UBERON:0002372	87.72	gold quality
parietal pleura	UBERON:0002400	87.65	gold quality
hair follicle	UBERON:0002073	87.59	gold quality
trabecular bone tissue	UBERON:0002483	87.43	gold quality
visceral pleura	UBERON:0002401	87.34	gold quality
upper leg skin	UBERON:0004262	87.32	gold quality
skin of abdomen	UBERON:0001416	87.31	gold quality
esophagus mucosa	UBERON:0002469	87.31	gold quality
colonic epithelium	UBERON:0000397	87.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	11.05
E-ANND-3	yes	5.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, EGR1, TP53

miRNA regulators (miRDB)

45 targeting TOPBP1, 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-8485	100.00	77.57	4731
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3145-3P	98.85	69.07	2031

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• interaction between the human papillomavirus 16 transcription/replication factor E2 and the DNA damage response protein TopBP1 (PMID:11934899)
• TopBP1 is regulated by PML by association and stabilization of the protein in response to IR-induced DNA damage (PMID:12773567)
• Both TopBP1 and BRCA1 specifically regulate the G(2)-M checkpoint, partially compensating each function. (PMID:12810625)
• hRad9/hHus1/hRad1 complex acts as a checkpoint sensor during S phase by rapidly localizing to sites of DNA damage and transducing checkpoint responses by facilitating proper localization of downstream checkpoint proteins, including TopBP1. (PMID:12941802)
• transcription of human MCM10 and TopBP1 is activated by transcription factors E2F1-3, but not by factors E2F4-7 (PMID:15195143)
• TopBP1 is a c-Abl-interacting protein and a repressor for c-Abl expression (PMID:15961388)
• TopBP1 plays a critical role in the maintenance of genomic stability during normal S phase as well as following genotoxic stress. (PMID:16314514)
• Data show that recombinant TopBP1 induces a large increase in the kinase activity of both Xenopus and human ATR-ATRIP. (PMID:16530042)
• Cooperative regulation of the TopBP1 promoter by Egr-1 and E2F. (PMID:16831524)
• These results suggest that while TopBP1 is a general regulator of ATR, Claspin operates downstream of TopBP1 to selectively regulate the Chk1-controlled branch of the genotoxic stress response. (PMID:16880517)
• A study evaluating several chromatin modification domains encoded by TopBP1, and the implications of these findings are discussed in the context of the DNA damage response and the understanding of TopBP1 function is presented. (PMID:16984230)
• findings show colocalization of TopBP1 and papillomavirus type 16 E2 on chromatin at late stages of mitosis, suggesting that TopBP1 could be the mitotic chromatin receptor for HPV16 E2 (PMID:17287259)
• TopBP1 necessary for the G(1)/S transition: one for activating cyclin E/CDK2 kinase and the other for loading replication components onto chromatin to initiate DNA synthesis. (PMID:17293600)
• This report demonstrates aberrant expression of the TopBP1 protein in breast carcinoma. We propose TOPBP1 as a breast cancer susceptibility gene. (PMID:17448016)
• Together, these results suggested that TopBP1 might be a mediator of DNA damage signaling from NBS1 to ATR and promote homologous recombination repair. (PMID:17765870)
• human TopBP1 is involved in the formation of the initiation complex of replication in human cells and is required for the recruitment of Cdc45 to origins of DNA replication (PMID:17887956)
• Interaction between SPBP and TopBP1 was found to be mediated by the ePHD domain of SPBP and the BRCT6 domain of TopBP1. (PMID:17913746)
• Cellular complementation experiments demonstrate that TopBP1-mediated ATR activation is required for checkpoint signaling and cellular viability (PMID:18519640)
• Miz1 and Myc affect the activity of the Atr checkpoint through their effect on TopBP1 chromatin association and stability. (PMID:18923429)
• HCLK2 functions in the same pathway as TopBP1 but that the two proteins regulate different steps in ATR activation. (PMID:19097996)
• Results suggest that a physiological level of TopBP1 is essential for normal G(1)/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior. (PMID:19289498)
• proliferating cell nuclear antigen, ATR, TopBP1, and Chk1 are recruited to chromatin in a MutLalpha- and MutSalpha-dependent fashion after N-methyl-N’-nitro-N-nitrosoguanidine treatment. (PMID:20029092)
• The interaction between TopBP1 and BACH1 is required for the extension of single-stranded DNA regions and RPA loading following replication stress, which is a prerequisite for the subsequent activation of replication checkpoint. (PMID:20159562)
• The phosphorylation at both serine residues occurs in vivo and is required for the efficient interaction with TopBP1 in vitro. (PMID:20545769)
• Data provide insights into how Ad modulates ATR signaling pathways by promoting TOPBP1 degradation during infection. (PMID:20566845)
• the crystal structure of the N-terminal region of human TopBP1, reveals an unexpected triple-BRCT domain structure. (PMID:20724438)
• the crystal structure of the TopBP1N-terminal region (residues 1-290) at 2.4A resolution was reported. (PMID:20858457)
• There is no evidence for the TOPBP1*Arg309Cys variant to confer an increased risk for breast cancer in the German population. (PMID:21108795)
• Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control. (PMID:21127055)
• TopBP1 deficiency in untransformed mouse and human primary cells induces cellular senescence rather than apoptosis. These results indicate that TopBP1 is essential for cell proliferation and maintenance of chromosomal integrity. (PMID:21149450)
• These results suggest that the localization of TopBP1 to the mitotic centrosomes is necessary for proper mitotic progression. (PMID:21291884)
• The specific TopBP1-MDC1 interaction was mediated by the fifth BRCT domain of TopBP1 and the Ser-Asp-Thr repeats of MDC1. TopBP1 accumulation at stalled replication forks was promoted by the H2AX/MDC1 signaling cascade. (PMID:21482717)
• Tethering DNA damage checkpoint mediator proteins topoisomerase IIbeta-binding protein 1 (TopBP1) and Claspin to DNA activates ataxia-telangiectasia mutated and RAD3-related (ATR) phosphorylation of checkpoint kinase 1 (Chk1). (PMID:21502314)
• findings show TopBP1 interacts with p53 hot spot mutants and NF-YA and promotes mutant p53 and p300 recruitment to NF-Y target gene promoters; TopBP1 mediates mutant p53 gain of function in cancer (PMID:21930790)
• Localisation of TopBP1 at DNA damage sites was noticed as early as 5 s following damage induction, whereas p54(nrb) and PSF localised there after 20 s. (PMID:22213094)
• data suggest that decreased level of TopBP1 mRNA and increased level of TopBP1 protein might be associated with progression of hereditary breast cancer (PMID:22544570)
• TopBP1 is likely to be involved in hereditary predisposition to breast and/or ovarian cancer (PMID:22708334)
• the affinity of Rad9 to TopBP1 correlates with the activation of the cellular DNA damage response and survival after DNA damage in HeLa cells. (PMID:22925454)
• An interaction between human papillomavirus 16 E2 and TopBP1 is required for optimum viral DNA replication and episomal genome establishment (PMID:22973044)
• our results showed that rs115160714 polymorphism can increase breast cancer risk and is associated with changes in TopBP1 expression. (PMID:23277395)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	topbp1	ENSDARG00000059322
mus_musculus	Topbp1	ENSMUSG00000032555
rattus_norvegicus	Topbp1	ENSRNOG00000009789

Paralogs (1): SLF1 (ENSG00000133302)

Protein

Protein identifiers

DNA topoisomerase 2-binding protein 1 — Q92547 (reviewed: Q92547)

Alternative names: DNA topoisomerase II-beta-binding protein 1, DNA topoisomerase II-binding protein 1

All UniProt accessions (3): A0A2R8YD63, Q92547, I3L1F2

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein that acts as a key protein-protein adapter in DNA replication and DNA repair. Composed of multiple BRCT domains, which specifically recognize and bind phosphorylated proteins, bringing proteins together into functional combinations. Required for DNA replication initiation but not for the formation of pre-replicative complexes or the elongation stages. Necessary for the loading of replication factors onto chromatin, including GMNC, CDC45, DNA polymerases and components of the GINS complex. Plays a central role in DNA repair by bridging proteins and promoting recruitment of proteins to DNA damage sites. Involved in double-strand break (DSB) repair via homologous recombination in S-phase by promoting the exchange between the DNA replication factor A (RPA) complex and RAD51. Mechanistically, TOPBP1 is recruited to DNA damage sites in S-phase via interaction with phosphorylated HTATSF1, and promotes the loading of RAD51, thereby facilitating RAD51 nucleofilaments formation and RPA displacement, followed by homologous recombination. Involved in microhomology-mediated end-joining (MMEJ) DNA repair by promoting recruitment of polymerase theta (POLQ) to DNA damage sites during mitosis. MMEJ is an alternative non-homologous end-joining (NHEJ) machinery that takes place during mitosis to repair DSBs in DNA that originate in S-phase. Recognizes and binds POLQ phosphorylated by PLK1, enabling its recruitment to DSBs for subsequent repair. Involved in G1 DNA damage checkpoint by acting as a molecular adapter that couples TP53BP1 and the 9-1-1 complex. In response to DNA damage, triggers the recruitment of checkpoint signaling proteins on chromatin, which activate the CHEK1 signaling pathway and block S-phase progression. Acts as an activator of the kinase activity of ATR. Also required for chromosomal stability when DSBs occur during mitosis by forming filamentous assemblies that bridge MDC1 and tether broken chromosomes during mitosis. Together with CIP2A, plays an essential role in the response to genome instability generated by the presence of acentric chromosome fragments derived from shattered chromosomes within micronuclei. Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, the CIP2A-TOPBP1 complex tethers chromosome fragments during mitosis to ensure clustered segregation of the fragments to a single daughter cell nucleus, facilitating re-ligation with limited chromosome scattering and loss. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters, thereby down-regulating E2F1 activity and inhibiting E2F1-dependent apoptosis during G1/S transition and after DNA damage.

Subunit / interactions. Interacts (via BRCT domains 1 and 2) with (phosphorylated) MDC1; promoting TOPBP1 recruitment to DNA damage sites during mitosis. Interacts (via BRCT domains 7 and 8) with (autophosphorylated) ATR; promoting activation of ATR. Interacts (via BRCT domains 7 and 8) with (phosphorylated) POLQ; specifically binds POLQ phosphorylated by PLK1, promoting POLQ recruitment to DNA damage sites. Interacts (via BRCT domains 1 and 2) with (phosphorylated) RAD9A. Interacts (via BRCT domain 2) with (phosphorylated) TP53BP1. Interacts (via BRCT domain 2) with (phosphorylated) HTATSF1. Interacts (via BRCT domains 7 and 8) with (phosphorylated) RAD51; promoting RAD51 recruitment to damaged chromatin. Interacts with CIP2A; forming the CIP2A-TOPBP1 complex. Interacts with POLE. Interacts with UBR5. Interacts with E2F1. Interacts with PML. Interacts with SMARCA2. Interacts with SMARCA4. Interacts with RHNO1. May interact with TOP2B. Interacts with TICRR. Interacts with HELB. Interacts (via residues 1233-1522) with RECQL4.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle pole.

Tissue specificity. Highly expressed in heart, brain, placenta, lung and kidney.

Post-translational modifications. Phosphorylated on serine and threonine residues in response to X-ray irradiation. Ubiquitinated and degraded by the proteasome. X-ray irradiation reduces ubiquitination. Deubiquitinated by USP13; leading to TOPBP1 stabilizion and activation of the ATR-TOPBP1 axis pathway.

Domain organisation. Some BRCT domains specifically recognize and bind phosphoserine/phosphothreonine marks on proteins. BRCT domains 1 and 2 bind phosphorylated MDC1 and RAD9A. BRCT domain 2 binds phosphorylated HTATSF1 and TP53BP1. BRCT domains 7 and 8 bind phosphorylated ATR, POLQ and RAD51.

Induction. Up-regulated during the S phase of the cell cycle. Up-regulated by E2F1 and interferon.

Similarity. Belongs to the TOPBP1 family.

RefSeq proteins (2): NP_001350818, NP_008958* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001357	BRCT_dom	Domain
IPR035960	Secretoglobin_sf	Homologous_superfamily
IPR036420	BRCT_dom_sf	Homologous_superfamily
IPR044737	TopBP1_BRCT_1	Domain
IPR049542	TopBP1-like_BRCT0	Domain
IPR049936	TopBP1_BRCT_8	Domain
IPR057595	TopB1_SLF1_BRCT	Domain
IPR059215	BRCT2_TopBP1-like	Domain

Pfam: PF00533, PF21298, PF23294

UniProt features (139 total): helix 46, strand 36, modified residue 13, mutagenesis site 11, turn 10, domain 8, region of interest 4, compositionally biased region 3, sequence variant 3, short sequence motif 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
3PD7	X-RAY DIFFRACTION	1.26
3JVE	X-RAY DIFFRACTION	1.34
9MAT	X-RAY DIFFRACTION	1.65
7CMZ	X-RAY DIFFRACTION	1.7
3UEN	X-RAY DIFFRACTION	1.9
3AL2	X-RAY DIFFRACTION	2
3AL3	X-RAY DIFFRACTION	2.15
3OLC	X-RAY DIFFRACTION	2.4
9MAW	X-RAY DIFFRACTION	2.45
2XNK	X-RAY DIFFRACTION	2.6
3UEO	X-RAY DIFFRACTION	2.6
2XNH	X-RAY DIFFRACTION	2.8
6RML	X-RAY DIFFRACTION	2.81
6RMM	X-RAY DIFFRACTION	3.53
8OK2	ELECTRON MICROSCOPY	4.1
1WF6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92547-F1	66.63	0.27

Functional residue map

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

Post-translational modifications (13): 298, 301, 779, 848, 860, 861, 864, 886, 888, 1002, 1062, 1064, 1504

Mutagenesis-validated functional residues (11):

Position	Phenotype
155	impaired interaction with phosphorylated mdc1. does not affect interaction with phosphorylated tp53bp1.
250	abolished interaction with phosphorylated htatsf1.
250	abolished interaction with phosphorylated tp53bp1.
564	does not affect interaction with mdc1.
681–682	decreased interaction with mdc1.
704	decreased interaction with mdc1. does not affect interaction with phosphorylated htatsf1.
837–839	decreased interaction with cip2a.
1273	decreased interaction with autophosphorylated atr.
1280	decreased interaction with autophosphorylated atr.
1317	does not affect interaction with phosphorylated htatsf1.
1317	decreased interaction with autophosphorylated atr.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
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-9709570	Impaired BRCA2 binding to RAD51

MSigDB gene sets: 342 (showing top): PID_FANCONI_PATHWAY, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, MODULE_451, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, PAL_PRMT5_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_CELL_CYCLE_PHASE_TRANSITION, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN

GO Biological Process (18): DNA replication checkpoint signaling (GO:0000076), DNA damage checkpoint signaling (GO:0000077), double-strand break repair via homologous recombination (GO:0000724), DNA metabolic process (GO:0006259), DNA replication initiation (GO:0006270), DNA repair (GO:0006281), DNA damage response (GO:0006974), mitotic G2 DNA damage checkpoint signaling (GO:0007095), response to ionizing radiation (GO:0010212), mitotic DNA replication checkpoint signaling (GO:0033314), homologous recombination (GO:0035825), chromosome organization (GO:0051276), double-strand break repair via classical nonhomologous end joining (GO:0097680), double-strand break repair via alternative nonhomologous end joining (GO:0097681), broken chromosome clustering (GO:0141112), protein localization to site of double-strand break (GO:1990166), double-strand break repair (GO:0006302), chromatin organization (GO:0006325)

GO Molecular Function (6): DNA binding (GO:0003677), identical protein binding (GO:0042802), protein serine/threonine kinase activator activity (GO:0043539), phosphorylation-dependent protein binding (GO:0140031), chromatin-protein adaptor activity (GO:0140463), protein binding (GO:0005515)

GO Cellular Component (16): condensed nuclear chromosome (GO:0000794), spindle pole (GO:0000922), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), centrosome (GO:0005813), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), nuclear body (GO:0016604), PML body (GO:0016605), site of double-strand break (GO:0035861), BRCA1-B complex (GO:0070532), site of DNA damage (GO:0090734), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	2
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
G2/M Checkpoints	1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membraneless organelle	3
DNA integrity checkpoint signaling	2
DNA metabolic process	2
DNA damage response	2
mitotic G2/M transition checkpoint	2
double-strand break repair via nonhomologous end joining	2
signal transduction in response to DNA damage	1
recombinational repair	1
double-strand break repair	1
nucleic acid metabolic process	1
DNA-templated DNA replication	1
cellular response to stress	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
response to radiation	1
DNA replication checkpoint signaling	1
mitotic cell cycle	1
mitotic DNA integrity checkpoint signaling	1
DNA recombination	1
organelle organization	1
chromosome organization	1
protein localization to chromosome	1
DNA repair	1
cellular component organization	1
nucleic acid binding	1
protein binding	1
protein serine/threonine kinase activity	1
protein kinase activator activity	1
modification-dependent protein binding	1
chromatin binding	1
chromatin organization	1
protein-macromolecule adaptor activity	1
binding	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1
spindle	1
germ cell nucleus	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2262 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOPBP1	TICRR	Q7Z2Z1	999
TOPBP1	ATRIP	Q8WXE1	998
TOPBP1	RAD9A	Q99638	996
TOPBP1	CDC45	O75419	995
TOPBP1	HUS1	O60921	990
TOPBP1	BRIP1	Q9BX63	985
TOPBP1	CLSPN	Q9HAW4	977
TOPBP1	MCM10	Q7L590	965
TOPBP1	MDC1	Q14676	950
TOPBP1	SLX4	Q8IY92	950
TOPBP1	E2F1	Q01094	946
TOPBP1	RAD17	O75943	939
TOPBP1	RECQL4	O94761	939
TOPBP1	TOP2B	Q02880	937
TOPBP1	CHEK1	O14757	917

IntAct

85 interactions, top by confidence:

A	B	Type	Score
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
ZBTB17	MYC	psi-mi:“MI:0915”(physical association)	0.780
TOPBP1	E2F1	psi-mi:“MI:0915”(physical association)	0.700
E2F1	TOPBP1	psi-mi:“MI:0915”(physical association)	0.700
TOPBP1	E2F1	psi-mi:“MI:0407”(direct interaction)	0.700
TOPBP1	E2	psi-mi:“MI:0915”(physical association)	0.670
TOPBP1	E2	psi-mi:“MI:0407”(direct interaction)	0.670
TOPBP1	TCF20	psi-mi:“MI:0915”(physical association)	0.650
TOPBP1	TCF20	psi-mi:“MI:0914”(association)	0.650
TOPBP1	CDC45	psi-mi:“MI:0915”(physical association)	0.540
CDC45	TOPBP1	psi-mi:“MI:0407”(direct interaction)	0.540
CDC45	TOPBP1	psi-mi:“MI:0915”(physical association)	0.540
AKT1	TOPBP1	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
AKT1	TOPBP1	psi-mi:“MI:0915”(physical association)	0.540
TOPBP1	TOPBP1	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (2995): TOPBP1 (Affinity Capture-Western), TOPBP1 (Affinity Capture-MS), TOPBP1 (Affinity Capture-MS), GINS1 (Two-hybrid), TOPBP1 (Reconstituted Complex), TOPBP1 (Affinity Capture-MS), TOPBP1 (Affinity Capture-Western), ERCC2 (Co-fractionation), TOPBP1 (Co-fractionation), TOPBP1 (Affinity Capture-Western), TOPBP1 (Affinity Capture-Western), TOPBP1 (Proximity Label-MS), TOPBP1 (Affinity Capture-MS), PPHLN1 (Two-hybrid), SMARCAD1 (Two-hybrid)

ESM2 similar proteins: A0A1P8ASY1, A2YP56, A3BMN9, B8BHK8, C5H8J1, D3IUT5, F4I9Q5, F4JF14, F4KEC6, O60566, O70445, Q0H8D7, Q5BPT4, Q5RET3, Q64MA3, Q68FQ7, Q6PD74, Q6Q4D0, Q6XV80, Q6ZQF0, Q7XD82, Q7Y1C4, Q7Y1C5, Q7Y1I7, Q7ZZY3, Q800K6, Q84M98, Q8GYU3, Q8VY10, Q8W475, Q92547, Q99728, Q9C6G0, Q9DDT2, Q9DE07, Q9FHA3, Q9FY74, Q9FYG2, Q9LPD2, Q9LXN4

Diamond homologs: A0JNA8, Q14676, Q5PSV9, Q5TM68, Q5U2M8, Q5XIY8, Q6NZQ4, Q6ZQF0, Q6ZW49, Q767L8, Q7YR40, Q7ZZY3, Q800K6, Q90WJ3, Q92547, A0A0G2JTR4, A2AWP8, A6QNS3, Q07139, Q12979, Q1ZXH8, Q29RM4, Q5R5M3, Q5SSL4, Q9H8V3, Q9HCE6, P32372, Q8C033, Q96PE2

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
TOPBP1	up-regulates	ATRIP	binding
FANCM	up-regulates	TOPBP1	relocalization
MUTYH	up-regulates	TOPBP1	binding
RAD1	up-regulates	TOPBP1	binding
RAD9A	up-regulates	TOPBP1	binding
TOPBP1	“up-regulates activity”	ATR	binding
PHF8	“up-regulates quantity by stabilization”	TOPBP1	binding
TOPBP1	“form complex”	“BRCA1-B complex”	binding
UBR5	“down-regulates quantity by destabilization”	TOPBP1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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
Impaired BRCA2 binding to RAD51	5	30.9×	1e-04
HDR through Single Strand Annealing (SSA)	5	29.3×	1e-04
Presynaptic phase of homologous DNA pairing and strand exchange	5	27.2×	1e-04
Processing of DNA double-strand break ends	9	20.6×	2e-07
G2/M DNA damage checkpoint	8	19.2×	2e-06
G2/M Checkpoints	6	16.1×	2e-04
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	14.6×	1e-03
Regulation of TP53 Activity through Phosphorylation	6	14.1×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
DNA damage checkpoint signaling	6	40.5×	4e-06
chromatin remodeling	8	10.1×	3e-04
DNA damage response	8	7.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	184
Likely benign	20
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

4596 predictions. Top by Δscore:

Variant	Effect	Δscore
3:133608869:AAACC:A	donor_loss	1.0000
3:133608870:AAC:A	donor_loss	1.0000
3:133608871:ACCT:A	donor_loss	1.0000
3:133608872:C:CT	donor_loss	1.0000
3:133608959:CTCC:C	acceptor_gain	1.0000
3:133608963:C:CC	acceptor_gain	1.0000
3:133612385:ACACC:A	donor_loss	1.0000
3:133612386:CACC:C	donor_loss	1.0000
3:133612550:CACCT:C	acceptor_gain	1.0000
3:133612551:ACCT:A	acceptor_loss	1.0000
3:133612552:CC:C	acceptor_loss	1.0000
3:133612553:C:CA	acceptor_loss	1.0000
3:133612554:T:C	acceptor_gain	1.0000
3:133616817:G:C	donor_gain	1.0000
3:133618211:AC:A	donor_gain	1.0000
3:133618212:CC:C	donor_gain	1.0000
3:133618351:C:A	donor_gain	1.0000
3:133619793:A:AC	donor_gain	1.0000
3:133619794:C:CC	donor_gain	1.0000
3:133620178:T:TA	donor_gain	1.0000
3:133620343:CAGAA:C	acceptor_gain	1.0000
3:133620348:C:CC	acceptor_gain	1.0000
3:133620349:T:C	acceptor_gain	1.0000
3:133620349:T:TC	acceptor_gain	1.0000
3:133623085:TTTTA:T	donor_loss	1.0000
3:133623086:TTTAC:T	donor_loss	1.0000
3:133623087:TTACC:T	donor_loss	1.0000
3:133623088:TAC:T	donor_loss	1.0000
3:133623089:A:AT	donor_loss	1.0000
3:133623092:T:TA	donor_gain	1.0000

AlphaMissense

10046 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:133655310:A:G	L241P	1.000
3:133611126:A:G	W1351R	0.999
3:133611126:A:T	W1351R	0.999
3:133618372:A:G	W1145R	0.999
3:133618372:A:T	W1145R	0.999
3:133624063:A:G	W973R	0.999
3:133624063:A:T	W973R	0.999
3:133624074:A:T	V969D	0.999
3:133649611:A:G	W426R	0.999
3:133649611:A:T	W426R	0.999
3:133653471:A:G	W266R	0.999
3:133653471:A:T	W266R	0.999
3:133653506:G:T	A254D	0.999
3:133656784:A:G	L146P	0.999
3:133608650:A:G	L1437P	0.998
3:133608892:A:G	L1415P	0.998
3:133612438:A:G	L1329P	0.998
3:133618365:T:C	D1147G	0.998
3:133618370:C:A	W1145C	0.998
3:133618370:C:G	W1145C	0.998
3:133624061:C:A	W973C	0.998
3:133624061:C:G	W973C	0.998
3:133640108:A:G	L695P	0.998
3:133640116:A:C	S692R	0.998
3:133640116:A:T	S692R	0.998
3:133640118:T:G	S692R	0.998
3:133649609:C:A	W426C	0.998
3:133649609:C:G	W426C	0.998
3:133653457:A:C	S270R	0.998
3:133653457:A:T	S270R	0.998

dbSNP variants (sampled 300 via entrez): RS1000120619 (3:133643014 G>A), RS1000175823 (3:133642729 CTTAT>C,CTTATTTAT), RS1000186276 (3:133658937 C>T), RS1000225256 (3:133608049 T>C,G), RS1000227139 (3:133613778 C>G,T), RS1000230377 (3:133621903 A>T), RS1000284092 (3:133659533 C>T), RS1000349282 (3:133646049 A>G), RS1000371282 (3:133629124 A>G), RS1000383318 (3:133602121 A>G), RS1000478651 (3:133626914 G>A,C), RS1000534099 (3:133639248 T>C), RS1000546837 (3:133610344 T>G), RS1000582584 (3:133617378 C>A), RS1000599423 (3:133662581 T>C)

Disease associations

OMIM: gene MIM:607760 | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
pulmonary arterial hypertension	No Known Disease Relationship	AD

Mondo (1): pulmonary arterial hypertension (MONDO:0015924)

Orphanet (2): Pulmonary arterial hypertension (Orphanet:182090), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000301_17	Iron status biomarkers	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004461	iron biomarker measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3175 (SINGLE PROTEIN), CHEMBL6066578 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	3
bisphenol A	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression, increases expression	1
FR900359	decreases phosphorylation	1
pradimicin-IRD	decreases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
trichostatin A	affects expression	1
riddelliine	decreases expression, increases metabolic processing	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
quinoline yellow	increases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
cadmium acetate	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
abrine	decreases expression	1
Troglitazone	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	decreases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	affects cotreatment, decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	decreases response to substance, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL814721	Binding	In vitro inhibition of Topoisomerase II-mediated DNA cleavage using supercoiled pBR322 plasmid DNA.	Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial