Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1K4J80)

• DOT Name: BRCA1-A complex subunit Abraxas 1 (ABRAXAS1)
• Synonyms: Coiled-coil domain-containing protein 98; Protein FAM175A
• Gene Name: ABRAXAS1
• Related Disease:
  Adult lymphoma
  Lymphoma
  Malignant soft tissue neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pediatric lymphoma
  Sarcoma
  Hereditary breast carcinoma
  Female hypogonadism
• UniProt ID: ABRX1_HUMAN
• PDB ID: 4JLU; 4U4A; 4Y18; 4Y2G
• Pfam ID: PF21125
• Sequence:
  MEGESTSAVLSGFVLGALAFQHLNTDSDTEGFLLGEVKGEAKNSITDSQMDDVEVVYTID
  IQKYIPCYQLFSFYNSSGEVNEQALKKILSNVKKNVVGWYKFRRHSDQIMTFRERLLHKN
  LQEHFSNQDLVFLLLTPSIITESCSTHRLEHSLYKPQKGLFHRVPLVVANLGMSEQLGYK
  TVSGSCMSTGFSRAVQTHSSKFFEEDGSLKEVHKINEMYASLQEELKSICKKVEDSEQAV
  DKLVKDVNRLKREIEKRRGAQIQAAREKNIQKDPQENIFLCQALRTFFPNSEFLHSCVMS
  LKNRHVSKSSCNYNHHLDVVDNLTLMVEHTDIPEASPASTPQIIKHKALDLDDRWQFKRS
  RLLDTQDKRSKADTGSSNQDKASKMSSPETDEEIEKMKGFGEYSRSPTF
• Function: Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX.
• 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[1]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[1]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[1]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[2]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[3]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[1]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[1]
Hereditary breast carcinoma	DISAEZT5	moderate	Biomarker	[3]
Female hypogonadism	DISWASB4	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[9]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of BRCA1-A complex subunit Abraxas 1 (ABRAXAS1).	[14]

References

• [1] Kaposi Sarcoma in Association With an Extracavitary Primary Effusion Lymphoma Showing Unusual Intravascular Involvement: Report of a Case Harboring a FAM175A Germline Mutation.Am J Dermatopathol. 2020 Jan;42(1):55-60. doi: 10.1097/DAD.0000000000001491.
• [2] Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.Clin Cancer Res. 2014 Feb 1;20(3):764-75. doi: 10.1158/1078-0432.CCR-13-2287. Epub 2013 Nov 15.
• [3] Evaluation of the BRCA1 interacting genes RAP80 and CCDC98 in familial breast cancer susceptibility.Breast Cancer Res Treat. 2009 Jan;113(2):371-6. doi: 10.1007/s10549-008-9933-4. Epub 2008 Feb 13.
• [4] Mutational analysis of theFAM175A gene in patients with premature ovarian insufficiency.Reprod Biomed Online. 2019 Jun;38(6):943-950. doi: 10.1016/j.rbmo.2019.02.006. Epub 2019 Feb 28.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] 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.
• [10] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] 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.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.