Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOY7FNT)

• DOT Name: BRISC and BRCA1-A complex member 2 (BABAM2)
• Synonyms: BRCA1-A complex subunit BRE; BRCA1/BRCA2-containing complex subunit 45; Brain and reproductive organ-expressed protein
• Gene Name: BABAM2
• Related Disease:
  Acute monocytic leukemia
  Breast cancer
  Breast carcinoma
  Epilepsy, idiopathic generalized
  Epithelial ovarian cancer
  Focal epilepsy
  Glioma
  Gout
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Triple negative breast cancer
  Uterine fibroids
  Acute myelogenous leukaemia
  Bipolar disorder
• UniProt ID: BABA2_HUMAN
• PDB ID: 6H3C; 6R8F
• Pfam ID: PF06113
• Sequence:
  MSPEVALNRISPMLSPFISSVVRNGKVGLDATNCLRITDLKSGCTSLTPGPNCDRFKLHI
  PYAGETLKWDIIFNAQYPELPPDFIFGEDAEFLPDPSALQNLASWNPSNPECLLLVVKEL
  VQQYHQFQCSRLRESSRLMFEYQTLLEEPQYGENMEIYAGKKNNWTGEFSARFLLKLPVD
  FSNIPTYLLKDVNEDPGEDVALLSVSFEDTEATQVYPKLYLSPRIEHALGGSSALHIPAF
  PGGGCLIDYVPQVCHLLTNKVQYVIQGYHKRREYIAAFLSHFGTGVVEYDAEGFTKLTLL
  LMWKDFCFLVHIDLPLFFPRDQPTLTFQSVYHFTNSGQLYSQAQKNYPYSPRWDGNEMAK
  RAKAYFKTFVPQFQEAAFANGKL
• 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 acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates. Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1. The BRISC complex 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. May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF-alpha signaling through its interactions with TNFRSF1A; however these effects may be indirect.
• Tissue Specificity: Expressed in all cell lines examined. Highly expressed in placenta.
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[4]
Focal epilepsy	DIS4LY5L	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Gout	DISHC0U7	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[9]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[10]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[11]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Genetic Variation	[12]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[24]
biochanin A	DM0HPWY	Investigative	biochanin A increases the expression of BRISC and BRCA1-A complex member 2 (BABAM2).	[25]

References

• [1] High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9-positive patients.Blood. 2011 Nov 17;118(20):5613-21. doi: 10.1182/blood-2011-06-359182. Epub 2011 Sep 21.
• [2] Expression of the BRCA1 complex member BRE predicts disease free survival in breast cancer.Breast Cancer Res Treat. 2012 Aug;135(1):125-33. doi: 10.1007/s10549-012-2122-5. Epub 2012 Jun 16.
• [3] Exclusion of linkage of genetic focal sharp waves to the HLA region on chromosome 6p in families with benign partial epilepsy with centrotemporal sharp waves.Neuropediatrics. 1993 Aug;24(4):208-10. doi: 10.1055/s-2008-1071541.
• [4] Pharmacogenomics in epithelial ovarian cancer first-line treatment outcome: validation of GWAS-associated NRG3 rs1649942 and BRE rs7572644 variants in an independent cohort.Pharmacogenomics J. 2019 Feb;19(1):25-32. doi: 10.1038/s41397-018-0056-y. Epub 2018 Oct 5.
• [5] Over-expression of the long non-coding RNA HOTTIP inhibits glioma cell growth by BRE.J Exp Clin Cancer Res. 2016 Oct 12;35(1):162. doi: 10.1186/s13046-016-0431-y.
• [6] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [7] BRE over-expression promotes growth of hepatocellular carcinoma.Biochem Biophys Res Commun. 2010 Jan 15;391(3):1522-5. doi: 10.1016/j.bbrc.2009.12.111. Epub 2009 Dec 24.
• [8] High levels of -glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer.BMC Cancer. 2013 Feb 1;13:47. doi: 10.1186/1471-2407-13-47.
• [9] Long non-coding RNA BRE-AS1 represses non-small cell lung cancer cell growth and survival via up-regulating NR4A3.Arch Biochem Biophys. 2018 Dec 15;660:53-63. doi: 10.1016/j.abb.2018.09.013. Epub 2018 Sep 15.
• [10] 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.
• [11] Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.Nat Commun. 2019 Oct 24;10(1):4857. doi: 10.1038/s41467-019-12536-4.
• [12] High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome.Leukemia. 2010 Dec;24(12):2048-55. doi: 10.1038/leu.2010.211. Epub 2010 Sep 23.
• [13] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [18] 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.
• [19] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [20] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [21] 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.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.