Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT46QWL4)

• DOT Name: BRCA1-A complex subunit RAP80
• Synonyms: Receptor-associated protein 80; Retinoid X receptor-interacting protein 110; Ubiquitin interaction motif-containing protein 1
• Gene Name: UIMC1
• Related Disease: Schizophrenia
• UniProt ID: UIMC1_HUMAN
• PDB ID: 2MKF; 2MKG; 2N9E; 2RR9
• Pfam ID: PF18282
• Sequence:
  MPRRKKKVKEVSESRNLEKKDVETTSSVSVKRKRRLEDAFIVISDSDGEEPKEENGLQKT
  KTKQSNRAKCLAKRKIAQMTEEEQFALALKMSEQEAREVNSQEEEEEELLRKAIAESLNS
  CRPSDASATRSRPLATGPSSQSHQEKTTDSGLTEGIWQLVPPSLFKGSHISQGNEAEERE
  EPWDHTEKTEEEPVSGSSGSWDQSSQPVFENVNVKSFDRCTGHSAEHTQCGKPQESTGRG
  SAFLKAVQGSGDTSRHCLPTLADAKGLQDTGGTVNYFWGIPFCPDGVDPNQYTKVILCQL
  EVYQKSLKMAQRQLLNKKGFGEPVLPRPPSLIQNECGQGEQASEKNECISEDMGDEDKEE
  RQESRASDWHSKTKDFQESSIKSLKEKLLLEEEPTTSHGQSSQGIVEETSEEGNSVPASQ
  SVAALTSKRSLVLMPESSAEEITVCPETQLSSSETFDLEREVSPGSRDILDGVRIIMADK
  EVGNKEDAEKEVAISTFSSSNQVSCPLCDQCFPPTKIERHAMYCNGLMEEDTVLTRRQKE
  AKTKSDSGTAAQTSLDIDKNEKCYLCKSLVPFREYQCHVDSCLQLAKADQGDGPEGSGRA
  CSTVEGKWQQRLKNPKEKGHSEGRLLSFLEQSEHKTSDADIKSSETGAFRVPSPGMEEAG
  CSREMQSSFTRRDLNESPVKSFVSISEATDCLVDFKKQVTVQPGSRTRTKAGRGRRRKF
• Function: Ubiquitin-binding protein. Specifically recognizes and binds 'Lys-63'-linked ubiquitin. Plays a central role in the BRCA1-A complex by specifically binding '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. Also weakly binds monoubiquitin but with much less affinity than 'Lys-63'-linked ubiquitin. May interact with monoubiquitinated histones H2A and H2B; the relevance of such results is however unclear in vivo. Does not bind Lys-48'-linked ubiquitin. May indirectly act as a transcriptional repressor by inhibiting the interaction of NR6A1 with the corepressor NCOR1.
• Tissue Specificity: Expressed in testis, ovary, thymus and heart. Expressed in germ cells of the testis.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	No Known	Unknown	[1]

8 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 RAP80.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BRCA1-A complex subunit RAP80.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BRCA1-A complex subunit RAP80.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BRCA1-A complex subunit RAP80.	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the mutagenesis of BRCA1-A complex subunit RAP80.	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of BRCA1-A complex subunit RAP80.	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of BRCA1-A complex subunit RAP80.	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BRCA1-A complex subunit RAP80.	[11]

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 RAP80.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of BRCA1-A complex subunit RAP80.	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of BRCA1-A complex subunit RAP80.	[10]

References

• [1] Rare damaging variants in DNA repair and cell cycle pathways are associated with hippocampal and cognitive dysfunction: a combined genetic imaging study in first-episode treatment-naive patients with schizophrenia. Transl Psychiatry. 2017 Feb 14;7(2):e1028. doi: 10.1038/tp.2016.291.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Integrative genomics and pathway analysis identified prevalent FA-BRCA pathway alterations in arsenic-associated urinary bladder carcinoma: Chronic arsenic accumulation in cancer tissues hampers the FA-BRCA pathway. Genomics. 2020 Nov;112(6):5055-5065. doi: 10.1016/j.ygeno.2020.09.012. Epub 2020 Sep 10.
• [7] 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.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] 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.
• [10] 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.
• [11] 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.