Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAW1I4C)

• DOT Name: BRISC complex subunit Abraxas 2 (ABRAXAS2)
• Synonyms: Abraxas brother protein 1; Protein FAM175B
• Gene Name: ABRAXAS2
• Related Disease:
  Advanced cancer
  Esophageal squamous cell carcinoma
  Trichohepatoenteric syndrome
  Coronary atherosclerosis
  Coronary heart disease
  Myocardial infarction
  Myocardial ischemia
• UniProt ID: ABRX2_HUMAN
• PDB ID: 6H3C; 6R8F
• Pfam ID: PF21125
• Sequence:
  MAASISGYTFSAVCFHSANSNADHEGFLLGEVRQEETFSISDSQISNTEFLQVIEIHNHQ
  PCSKLFSFYDYASKVNEESLDRILKDRRKKVIGWYRFRRNTQQQMSYREQVLHKQLTRIL
  GVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPN
  TSQSYAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAE
  VNKLRRQITQRKNEKEQERRLQQAVLSRQMPSESLDPAFSPRMPSSGFAAEGRSTLGDAE
  ASDPPPPYSDFHPNNQESTLSHSRMERSVFMPRPQAVGSSNYASTSAGLKYPGSGADLPP
  PQRAAGDSGEDSDDSDYENLIDPTEPSNSEYSHSKDSRPMAHPDEDPRNTQTSQI
• Function: Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked polyubiquitin, leaving the last ubiquitin chain attached to its substrates. May act as a central scaffold protein that assembles the various components of the BRISC complex and retains them in the cytoplasm. Plays a role in regulating the onset of apoptosis via its role in modulating 'Lys-63'-linked ubiquitination of target proteins. 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 activities by enhancing its stability and cell surface expression. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination. Required for normal induction of p53/TP53 in response to DNA damage. Independent of the BRISC complex, promotes interaction between USP7 and p53/TP53, and thereby promotes deubiquitination of p53/TP53, preventing its degradation and resulting in increased p53/TP53-mediated transcription regulation and p53/TP53-dependent apoptosis in response to DNA damage.
• Tissue Specificity: Detected in heart muscle (at protein level). Detected in heart and muscle, and at much lower levels in brain .
• Reactome Pathway: Metalloprotease DUBs (R-HSA-5689901)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[2]
Coronary atherosclerosis	DISKNDYU	Limited	Altered Expression	[3]
Coronary heart disease	DIS5OIP1	Limited	Altered Expression	[3]
Myocardial infarction	DIS655KI	Limited	Altered Expression	[3]
Myocardial ischemia	DISFTVXF	Limited	Altered Expression	[3]

6 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 BRISC complex subunit Abraxas 2 (ABRAXAS2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[11]

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 decreases the methylation of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of BRISC complex subunit Abraxas 2 (ABRAXAS2).	[9]

References

• [1] FAM175B promotes apoptosis by inhibiting ATF4 ubiquitination in esophageal squamous cell carcinoma.Mol Oncol. 2019 May;13(5):1150-1165. doi: 10.1002/1878-0261.12474. Epub 2019 Mar 23.
• [2] ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination.EMBO J. 2019 Mar 15;38(6):e100376. doi: 10.15252/embj.2018100376. Epub 2019 Feb 20.
• [3] Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination.J Mol Cell Cardiol. 2011 Apr;50(4):652-61. doi: 10.1016/j.yjmcc.2010.12.015. Epub 2010 Dec 30.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] 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.
• [9] 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.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.