Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6UPZPD)

• DOT Name: DNA topoisomerase 2-binding protein 1 (TOPBP1)
• Synonyms: DNA topoisomerase II-beta-binding protein 1; TopBP1; DNA topoisomerase II-binding protein 1
• Gene Name: TOPBP1
• Related Disease:
  Advanced cancer
  Bloom syndrome
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Ductal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Hereditary breast carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Polycystic kidney disease 1
  Retinoblastoma
  Small lymphocytic lymphoma
  Carcinoma
  Epithelial ovarian cancer
  Laryngeal carcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Bone osteosarcoma
  Chromosomal disorder
  Epileptic encephalopathy
  Leiomyosarcoma
  Malignant soft tissue neoplasm
  Osteosarcoma
  Sarcoma
  X-linked Opitz G/BBB syndrome
  Pulmonary arterial hypertension
• UniProt ID: TOPB1_HUMAN
• PDB ID: 1WF6; 2XNH; 2XNK; 3AL2; 3AL3; 3JVE; 3OLC; 3PD7; 3UEN; 3UEO; 6RML; 6RMM; 7CMZ
• Pfam ID: PF00533 ; PF12738 ; PF21298
• Sequence:
  MSRNDKEPFFVKFLKSSDNSKCFFKALESIKEFQSEEYLQIITEEEALKIKENDRSLYIC
  DPFSGVVFDHLKKLGCRIVGPQVVIFCMHHQRCVPRAEHPVYNMVMSDVTISCTSLEKEK
  REEVHKYVQMMGGRVYRDLNVSVTHLIAGEVGSKKYLVAANLKKPILLPSWIKTLWEKSQ
  EKKITRYTDINMEDFKCPIFLGCIICVTGLCGLDRKEVQQLTVKHGGQYMGQLKMNECTH
  LIVQEPKGQKYECAKRWNVHCVTTQWFFDSIEKGFCQDESIYKTEPRPEAKTMPNSSTPT
  SQINTIDSRTLSDVSNISNINASCVSESICNSLNSKLEPTLENLENLDVSAFQAPEDLLD
  GCRIYLCGFSGRKLDKLRRLINSGGGVRFNQLNEDVTHVIVGDYDDELKQFWNKSAHRPH
  VVGAKWLLECFSKGYMLSEEPYIHANYQPVEIPVSHKPESKAALLKKKNSSFSKKDFAPS
  EKHEQADEDLLSQYENGSSTVVEAKTSEARPFNDSTHAEPLNDSTHISLQEENQSSVSHC
  VPDVSTITEEGLFSQKSFLVLGFSNENESNIANIIKENAGKIMSLLSRTVADYAVVPLLG
  CEVEATVGEVVTNTWLVTCIDYQTLFDPKSNPLFTPVPVMTGMTPLEDCVISFSQCAGAE
  KESLTFLANLLGASVQEYFVRKSNAKKGMFASTHLILKERGGSKYEAAKKWNLPAVTIAW
  LLETARTGKRADESHFLIENSTKEERSLETEITNGINLNSDTAEHPGTRLQTHRKTVVTP
  LDMNRFQSKAFRAVVSQHARQVAASPAVGQPLQKEPSLHLDTPSKFLSKDKLFKPSFDVK
  DALAALETPGRPSQQKRKPSTPLSEVIVKNLQLALANSSRNAVALSASPQLKEAQSEKEE
  APKPLHKVVVCVSKKLSKKQSELNGIAASLGADYRWSFDETVTHFIYQGRPNDTNREYKS
  VKERGVHIVSEHWLLDCAQECKHLPESLYPHTYNPKMSLDISAVQDGRLCNSRLLSAVSS
  TKDDEPDPLILEENDVDNMATNNKESAPSNGSGKNDSKGVLTQTLEMRENFQKQLQEIMS
  ATSIVKPQGQRTSLSRSGCNSASSTPDSTRSARSGRSRVLEALRQSRQTVPDVNTEPSQN
  EQIIWDDPTAREERARLASNLQWPSCPTQYSELQVDIQNLEDSPFQKPLHDSEIAKQAVC
  DPGNIRVTEAPKHPISEELETPIKDSHLIPTPQAPSIAFPLANPPVAPHPREKIITIEET
  HEELKKQYIFQLSSLNPQERIDYCHLIEKLGGLVIEKQCFDPTCTHIVVGHPLRNEKYLA
  SVAAGKWVLHRSYLEACRTAGHFVQEEDYEWGSSSILDVLTGINVQQRRLALAAMRWRKK
  IQQRQESGIVEGAFSGWKVILHVDQSREAGFKRLLQSGGAKVLPGHSVPLFKEATHLFSD
  LNKLKPDDSGVNIAEAAAQNVYCLRTEYIADYLMQESPPHVENYCLPEAISFIQNNKELG
  TGLSQKRKAPTEKNKIKRPRVH
• 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.
• Tissue Specificity: Highly expressed in heart, brain, placenta, lung and kidney.
• KEGG Pathway: Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Bloom syndrome	DISKXQ7J	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[6]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[7]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[7]
Hereditary breast carcinoma	DISAEZT5	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[10]
Polycystic kidney disease 1	DIS9FB3R	Strong	Altered Expression	[11]
Retinoblastoma	DISVPNPB	Strong	Genetic Variation	[12]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[13]
Carcinoma	DISH9F1N	moderate	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[14]
Laryngeal carcinoma	DISNHCIV	moderate	Genetic Variation	[15]
Lung cancer	DISCM4YA	moderate	Biomarker	[16]
Lung carcinoma	DISTR26C	moderate	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[15]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[14]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[17]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[18]
Epileptic encephalopathy	DISZOCA3	Limited	Biomarker	[17]
Leiomyosarcoma	DIS6COXM	Limited	Altered Expression	[17]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Altered Expression	[17]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[17]
Sarcoma	DISZDG3U	Limited	Altered Expression	[17]
X-linked Opitz G/BBB syndrome	DISQ14EC	Limited	Biomarker	[17]
Pulmonary arterial hypertension	DISP8ZX5	No Known	Autosomal dominant	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	DNA topoisomerase 2-binding protein 1 (TOPBP1) affects the response to substance of Fluorouracil.	[39]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[24]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[26]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[27]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[28]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[29]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[34]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[35]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[36]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[37]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[38]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA topoisomerase 2-binding protein 1 (TOPBP1).	[32]

References

• [1] TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity.J Cell Biol. 2016 Feb 1;212(3):281-8. doi: 10.1083/jcb.201507042. Epub 2016 Jan 25.
• [2] Structural Insight into BLM Recognition by TopBP1.Structure. 2017 Oct 3;25(10):1582-1588.e3. doi: 10.1016/j.str.2017.08.005. Epub 2017 Sep 14.
• [3] Association between the c.*229C>T polymorphism of the topoisomerase II binding protein 1 (TopBP1) gene and breast cancer.Mol Biol Rep. 2013 May;40(5):3493-502. doi: 10.1007/s11033-012-2424-z. Epub 2013 Jan 1.
• [4] Regulation of p53 by TopBP1: a potential mechanism for p53 inactivation in cancer.Mol Cell Biol. 2009 May;29(10):2673-93. doi: 10.1128/MCB.01140-08. Epub 2009 Mar 16.
• [5] Novel somatic frameshift mutations of genes related to cell cycle and DNA damage response in gastric and colorectal cancers with microsatellite instability.Tumori. 2010 Nov-Dec;96(6):1004-9.
• [6] Expression of TopBP1 in hereditary breast cancer.Mol Biol Rep. 2012 Jul;39(7):7795-804. doi: 10.1007/s11033-012-1622-z. Epub 2012 Apr 28.
• [7] Topoisomerase II binding protein 1 c.*229C>T (rs115160714) gene polymorphism and endometrial cancer risk.Pathol Oncol Res. 2014 Jul;20(3):597-602. doi: 10.1007/s12253-013-9737-7. Epub 2013 Dec 18.
• [8] Topoisomerase II-binding protein 1 activates expression of E2F1 and p73 in HPV-positive cells for genome amplification upon epithelial differentiation.Oncogene. 2019 Apr;38(17):3274-3287. doi: 10.1038/s41388-018-0633-1. Epub 2019 Jan 10.
• [9] Calcein-acetoxymethy ester enhances the antitumor effects of doxorubicin in nonsmall cell lung cancer by regulating the TopBP1/p53RR pathway.Anticancer Drugs. 2017 Sep;28(8):861-868. doi: 10.1097/CAD.0000000000000527.
• [10] Interaction of polymorphisms in mitotic regulator genes with cigarette smoking and pancreatic cancer risk.Mol Carcinog. 2013 Nov;52 Suppl 1(0 1):E103-9. doi: 10.1002/mc.22037. Epub 2013 Jun 12.
• [11] Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage.Cancer Res. 2001 Nov 1;61(21):8022-31.
• [12] RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1.Genes Dev. 2016 Nov 15;30(22):2500-2512. doi: 10.1101/gad.288282.116.
• [13] Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis.Blood. 2008 Feb 1;111(3):1625-33. doi: 10.1182/blood-2007-08-110130. Epub 2007 Nov 15.
• [14] Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer.Eur J Cancer. 2006 Oct;42(15):2647-52. doi: 10.1016/j.ejca.2006.05.030. Epub 2006 Aug 23.
• [15] The c.*229C?T gene polymorphism in 3'UTR region of the topoisomerase II binding protein 1 gene and LOH in BRCA1/2 regions and their effect on the risk and progression of human laryngeal carcinoma.Tumour Biol. 2016 Apr;37(4):4541-57. doi: 10.1007/s13277-015-4276-3. Epub 2015 Oct 27.
• [16] TopBP1 and Claspin contribute to the radioresistance of lung cancer brain metastases.Mol Cancer. 2014 Sep 12;13:211. doi: 10.1186/1476-4598-13-211.
• [17] TopBP1 promotes malignant progression and correlates with poor prognosis in osteosarcoma.Eur Rev Med Pharmacol Sci. 2017 Sep;21(18):4022-4031.
• [18] TOPBP1(Dpb11) plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1(Rad9).J Cell Biol. 2017 Mar 6;216(3):623-639. doi: 10.1083/jcb.201607031. Epub 2017 Feb 22.
• [19] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [20] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [21] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [22] Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chem Biol Interact. 2023 Feb 1;371:110342. doi: 10.1016/j.cbi.2023.110342. Epub 2023 Jan 10.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [28] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [29] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [30] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [31] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [32] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [33] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [34] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [35] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [36] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [37] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [38] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [39] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.