Details of Drug Off-Target (DOT)

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

• DOT Name: DNA repair protein REV1 (REV1)
• Synonyms: EC 2.7.7.-; Alpha integrin-binding protein 80; AIBP80; Rev1-like terminal deoxycytidyl transferase
• Gene Name: REV1
• Related Disease:
  Advanced cancer
  Brucellosis
  Fanconi anemia complementation group A
  Fanconi's anemia
  Fibrosarcoma
  Leukopenia
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Breast cancer
  Breast carcinoma
  Cervical carcinoma
  Human papillomavirus infection
  Chromosomal disorder
• UniProt ID: REV1_HUMAN
• PDB ID: 2EBW; 2LSI; 2LSK; 2LSY; 2N1G; 3GQC; 3VU7; 4BA9; 4EXT; 4GK0; 4GK5; 5VZM; 6ASR; 6AXD; 6WS0; 6WS5
• EC Number: 2.7.7.-
• Pfam ID: PF00533 ; PF00817 ; PF11799 ; PF21704 ; PF16727 ; PF14377
• Sequence:
  MRRGGWRKRAENDGWETWGGYMAAKVQKLEEQFRSDAAMQKDGTSSTIFSGVAIYVNGYT
  DPSAEELRKLMMLHGGQYHVYYSRSKTTHIIATNLPNAKIKELKGEKVIRPEWIVESIKA
  GRLLSYIPYQLYTKQSSVQKGLSFNPVCRPEDPLPGPSNIAKQLNNRVNHIVKKIETENE
  VKVNGMNSWNEEDENNDFSFVDLEQTSPGRKQNGIPHPRGSTAIFNGHTPSSNGALKTQD
  CLVPMVNSVASRLSPAFSQEEDKAEKSSTDFRDCTLQQLQQSTRNTDALRNPHRTNSFSL
  SPLHSNTKINGAHHSTVQGPSSTKSTSSVSTFSKAAPSVPSKPSDCNFISNFYSHSRLHH
  ISMWKCELTEFVNTLQRQSNGIFPGREKLKKMKTGRSALVVTDTGDMSVLNSPRHQSCIM
  HVDMDCFFVSVGIRNRPDLKGKPVAVTSNRGTGRAPLRPGANPQLEWQYYQNKILKGKAA
  DIPDSSLWENPDSAQANGIDSVLSRAEIASCSYEARQLGIKNGMFFGHAKQLCPNLQAVP
  YDFHAYKEVAQTLYETLASYTHNIEAVSCDEALVDITEILAETKLTPDEFANAVRMEIKD
  QTKCAASVGIGSNILLARMATRKAKPDGQYHLKPEEVDDFIRGQLVTNLPGVGHSMESKL
  ASLGIKTCGDLQYMTMAKLQKEFGPKTGQMLYRFCRGLDDRPVRTEKERKSVSAEINYGI
  RFTQPKEAEAFLLSLSEEIQRRLEATGMKGKRLTLKIMVRKPGAPVETAKFGGHGICDNI
  ARTVTLDQATDNAKIIGKAMLNMFHTMKLNISDMRGVGIHVNQLVPTNLNPSTCPSRPSV
  QSSHFPSGSYSVRDVFQVQKAKKSTEEEHKEVFRAAVDLEISSASRTCTFLPPFPAHLPT
  SPDTNKAESSGKWNGLHTPVSVQSRLNLSIEVPSPSQLDQSVLEALPPDLREQVEQVCAV
  QQAESHGDKKKEPVNGCNTGILPQPVGTVLLQIPEPQESNSDAGINLIALPAFSQVDPEV
  FAALPAELQRELKAAYDQRQRQGENSTHQQSASASVPKNPLLHLKAAVKEKKRNKKKKTI
  GSPKRIQSPLNNKLLNSPAKTLPGACGSPQKLIDGFLKHEGPPAEKPLEELSASTSGVPG
  LSSLQSDPAGCVRPPAPNLAGAVEFNDVKTLLREWITTISDPMEEDILQVVKYCTDLIEE
  KDLEKLDLVIKYMKRLMQQSVESVWNMAFDFILDNVQVVLQQTYGSTLKVT
• Function: Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Translesion synthesis by POLK (R-HSA-5655862)
  Translesion synthesis by POLI (R-HSA-5656121)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  Translesion synthesis by REV1 (R-HSA-110312)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Brucellosis	DISEAYGH	Strong	Biomarker	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[3]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[3]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[4]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[8]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[8]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[8]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	moderate	Biomarker	[9]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[9]
Cervical carcinoma	DIST4S00	moderate	Genetic Variation	[10]
Human papillomavirus infection	DISX61LX	moderate	Genetic Variation	[10]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA repair protein REV1 (REV1).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of DNA repair protein REV1 (REV1).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA repair protein REV1 (REV1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of DNA repair protein REV1 (REV1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA repair protein REV1 (REV1).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of DNA repair protein REV1 (REV1).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA repair protein REV1 (REV1).	[16]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of DNA repair protein REV1 (REV1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA repair protein REV1 (REV1).	[18]
Guanine	DMIWLJE	Phase 3	Guanine decreases the activity of DNA repair protein REV1 (REV1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DNA repair protein REV1 (REV1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA repair protein REV1 (REV1).	[23]

References

• [1] REV1-POL Inhibition and Cancer Therapy.Mol Cell. 2019 Aug 8;75(3):419-420. doi: 10.1016/j.molcel.2019.07.012.
• [2] GFP tagging of Brucella melitensis Rev1 allows the identification of vaccinated sheep.Transbound Emerg Dis. 2019 Jan;66(1):505-516. doi: 10.1111/tbed.13053. Epub 2018 Nov 26.
• [3] The roles of DNA polymerase and the Y family DNA polymerases in promoting or preventing genome instability.Mutat Res. 2013 Mar-Apr;743-744:97-110. doi: 10.1016/j.mrfmmm.2012.11.002. Epub 2012 Nov 26.
• [4] Identification of Small Molecule Translesion Synthesis Inhibitors That Target the Rev1-CT/RIR Protein-Protein Interaction.ACS Chem Biol. 2017 Jul 21;12(7):1903-1912. doi: 10.1021/acschembio.6b01144. Epub 2017 Jun 9.
• [5] Polymorphisms in translesion polymerase genes influence treatment outcome in malignant mesothelioma.Pharmacogenomics. 2014 May;15(7):941-50. doi: 10.2217/pgs.14.14.
• [6] Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men.Cancer Epidemiol. 2013 Dec;37(6):917-22. doi: 10.1016/j.canep.2013.08.003. Epub 2013 Sep 5.
• [7] A mega-analysis of genome-wide association studies for major depressive disorder.Mol Psychiatry. 2013 Apr;18(4):497-511. doi: 10.1038/mp.2012.21. Epub 2012 Apr 3.
• [8] Integrated ligand-receptor bioinformatic and in vitro functional analysis identifies active TGFA/EGFR signaling loop in papillary thyroid carcinomas.PLoS One. 2010 Sep 22;5(9):e12701. doi: 10.1371/journal.pone.0012701.
• [9] Intrinsic adriamycin resistance in p53-mutated breast cancer is related to the miR-30c/FANCF/REV1-mediated DNA damage response.Cell Death Dis. 2019 Sep 11;10(9):666. doi: 10.1038/s41419-019-1871-z.
• [10] REV1 genetic variants associated with the risk of cervical carcinoma.Eur J Epidemiol. 2008;23(6):403-9. doi: 10.1007/s10654-008-9251-5. Epub 2008 May 10.
• [11] Differential roles for DNA polymerases eta, zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links.Mol Cell Biol. 2010 Mar;30(5):1217-30. doi: 10.1128/MCB.00993-09. Epub 2009 Dec 22.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] 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.
• [14] Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chem Biol Interact. 2023 Feb 1;371:110342. doi: 10.1016/j.cbi.2023.110342. Epub 2023 Jan 10.
• [15] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Analysis of nucleotide insertion opposite 2,2,4-triamino-5(2H)-oxazolone by eukaryotic B- and Y-family DNA polymerases. Chem Res Toxicol. 2015 Jun 15;28(6):1307-16. doi: 10.1021/acs.chemrestox.5b00114. Epub 2015 Jun 3.
• [20] 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.
• [21] 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.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.