Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCFPER6)

• DOT Name: BRISC and BRCA1-A complex member 1 (BABAM1)
• Synonyms: Mediator of RAP80 interactions and targeting subunit of 40 kDa; New component of the BRCA1-A complex
• Gene Name: BABAM1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Fanconi anemia complementation group A
  Fanconi's anemia
  Lung adenocarcinoma
  Lung carcinoma
  Lung squamous cell carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Triple negative breast cancer
  Hereditary breast carcinoma
  Epithelial ovarian cancer
  Ovarian serous adenocarcinoma
• UniProt ID: BABA1_HUMAN
• PDB ID: 6H3C
• Sequence:
  MEVAEPSSPTEEEEEEEEHSAEPRPRTRSNPEGAEDRAVGAQASVGSRSEGEGEAASADD
  GSLNTSGAGPKSWQVPPPAPEVQIRTPRVNCPEKVIICLDLSEEMSLPKLESFNGSKTNA
  LNVSQKMIEMFVRTKHKIDKSHEFALVVVNDDTAWLSGLTSDPRELCSCLYDLETASCST
  FNLEGLFSLIQQKTELPVTENVQTIPPPYVVRTILVYSRPPCQPQFSLTEPMKKMFQCPY
  FFFDVVYIHNGTEEKEEEMSWKDMFAFMGSLDTKGTSYKYEVALAGPALELHNCMAKLLA
  HPLQRPCQSHASYSLLEEEDEAIEVEATV
• Function: Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it is required for the complex integrity and its localization at DSBs. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates. In these 2 complexes, it is probably required to maintain the stability of BABAM2 and help the 'Lys-63'-linked deubiquitinase activity mediated by BRCC3/BRCC36 component. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1. Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination.
• KEGG Pathway: Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Metalloprotease DUBs (R-HSA-5689901)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Genetic Variation	[2]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[2]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[3]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[2]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[2]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[2]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[4]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[5]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[2]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[6]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[7]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[8]
Ovarian serous adenocarcinoma	DISSU72Z	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BRISC and BRCA1-A complex member 1 (BABAM1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of BRISC and BRCA1-A complex member 1 (BABAM1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BRISC and BRCA1-A complex member 1 (BABAM1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of BRISC and BRCA1-A complex member 1 (BABAM1).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of BRISC and BRCA1-A complex member 1 (BABAM1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of BRISC and BRCA1-A complex member 1 (BABAM1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of BRISC and BRCA1-A complex member 1 (BABAM1).	[15]

References

• [1] Evaluating genome-wide association study-identified breast cancer risk variants in African-American women.PLoS One. 2013 Apr 8;8(4):e58350. doi: 10.1371/journal.pone.0058350. Print 2013.
• [2] Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.Cancer Res. 2016 Sep 1;76(17):5103-14. doi: 10.1158/0008-5472.CAN-15-2980. Epub 2016 Apr 20.
• [3] MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links.Genes Dev. 2015 Sep 15;29(18):1955-68. doi: 10.1101/gad.264192.115. Epub 2015 Sep 3.
• [4] GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.Nat Genet. 2013 Apr;45(4):362-70, 370e1-2. doi: 10.1038/ng.2564.
• [5] Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.Nat Genet. 2017 May;49(5):680-691. doi: 10.1038/ng.3826. Epub 2017 Mar 27.
• [6] Genetic evaluation of BRCA1 associated a complex genes with triple-negative breast cancer susceptibility in Chinese women.Oncotarget. 2016 Mar 1;7(9):9759-72. doi: 10.18632/oncotarget.7112.
• [7] Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families.Breast Cancer Res Treat. 2010 Feb;120(1):165-8. doi: 10.1007/s10549-009-0453-7. Epub 2009 Jul 2.
• [8] Common variants at 19p13 are associated with susceptibility to ovarian cancer.Nat Genet. 2010 Oct;42(10):880-4. doi: 10.1038/ng.666. Epub 2010 Sep 19.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] 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.