Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0OP8EJ)

• DOT Name: DNA polymerase zeta catalytic subunit (REV3L)
• Synonyms: EC 2.7.7.7; Protein reversionless 3-like; REV3-like; hREV3
• Gene Name: REV3L
• Related Disease:
  Breast neoplasm
  Glioma
  B-cell neoplasm
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Head-neck squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Stomach cancer
  Adult glioblastoma
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Fanconi anemia complementation group D2
  Glioblastoma multiforme
  Osteosarcoma
  Mobius syndrome
  Advanced cancer
  Mesothelioma
  Non-insulin dependent diabetes
  Psoriasis
  Psoriatic arthritis
  Rheumatoid arthritis
• UniProt ID: REV3L_HUMAN
• PDB ID: 3ABD; 3ABE; 3VU7; 4EXT; 4GK0; 4GK5; 5O8K; 6BC8; 6BCD; 6BI7; 6EKM; 6KEA; 6WS0; 6WS5
• EC Number: 2.7.7.7
• Pfam ID: PF00136 ; PF03104 ; PF15735 ; PF14260
• Sequence:
  MFSVRIVTADYYMASPLQGLDTCQSPLTQAPVKKVPVVRVFGATPAGQKTCLHLHGIFPY
  LYVPYDGYGQQPESYLSQMAFSIDRALNVALGNPSSTAQHVFKVSLVSGMPFYGYHEKER
  HFMKIYLYNPTMVKRICELLQSGAIMNKFYQPHEAHIPYLLQLFIDYNLYGMNLINLAAV
  KFRKARRKSNTLHATGSCKNHLSGNSLADTLFRWEQDEIPSSLILEGVEPQSTCELEVDA
  VAADILNRLDIEAQIGGNPGLQAIWEDEKQRRRNRNETSQMSQPESQDHRFVPATESEKK
  FQKRLQEILKQNDFSVTLSGSVDYSDGSQEFSAELTLHSEVLSPEMLQCTPANMVEVHKD
  KESSKGHTRHKVEEALINEEAILNLMENSQTFQPLTQRLSESPVFMDSSPDEALVHLLAG
  LESDGYRGERNRMPSPCRSFGNNKYPQNSDDEENEPQIEKEEMELSLVMSQRWDSNIEEH
  CAKKRSLCRNTHRSSTEDDDSSSGEEMEWSDNSLLLASLSIPQLDGTADENSDNPLNNEN
  SRTHSSVIATSKLSVKPSIFHKDAATLEPSSSAKITFQCKHTSALSSHVLNKEDLIEDLS
  QTNKNTEKGLDNSVTSFTNESTYSMKYPGSLSSTVHSENSHKENSKKEILPVSSCESSIF
  DYEEDIPSVTRQVPSRKYTNIRKIEKDSPFIHMHRHPNENTLGKNSFNFSDLNHSKNKVS
  SEGNEKGNSTALSSLFPSSFTENCELLSCSGENRTMVHSLNSTADESGLNKLKIRYEEFQ
  EHKTEKPSLSQQAAHYMFFPSVVLSNCLTRPQKLSPVTYKLQPGNKPSRLKLNKRKLAGH
  QETSTKSSETGSTKDNFIQNNPCNSNPEKDNALASDLTKTTRGAFENKTPTDGFIDCHFG
  DGTLETEQSFGLYGNKYTLRAKRKVNYETEDSESSFVTHNSKISLPHPMEIGESLDGTLK
  SRKRRKMSKKLPPVIIKYIIINRFRGRKNMLVKLGKIDSKEKQVILTEEKMELYKKLAPL
  KDFWPKVPDSPATKYPIYPLTPKKSHRRKSKHKSAKKKTGKQQRTNNENIKRTLSFRKKR
  SHAILSPPSPSYNAETEDCDLNYSDVMSKLGFLSERSTSPINSSPPRCWSPTDPRAEEIM
  AAAEKEAMLFKGPNVYKKTVNSRIGKTSRARAQIKKSKAKLANPSIVTKKRNKRNQTNKL
  VDDGKKKPRAKQKTNEKGTSRKHTTLKDEKIKSQSGAEVKFVLKHQNVSEFASSSGGSQL
  LFKQKDMPLMGSAVDHPLSASLPTGINAQQKLSGCFSSFLESKKSVDLQTFPSSRDDLHP
  SVVCNSIGPGVSKINVQRPHNQSAMFTLKESTLIQKNIFDLSNHLSQVAQNTQISSGMSS
  KIEDNANNIQRNYLSSIGKLSEYRNSLESKLDQAYTPNFLHCKDSQQQIVCIAEQSKHSE
  TCSPGNTASEESQMPNNCFVTSLRSPIKQIAWEQKQRGFILDMSNFKPERVKPRSLSEAI
  SQTKALSQCKNRNVSTPSAFGEGQSGLAVLKELLQKRQQKAQNANTTQDPLSNKHQPNKN
  ISGSLEHNKANKRTRSVTSPRKPRTPRSTKQKEKIPKLLKVDSLNLQNSSQLDNSVSDDS
  PIFFSDPGFESCYSLEDSLSPEHNYNFDINTIGQTGFCSFYSGSQFVPADQNLPQKFLSD
  AVQDLFPGQAIEKNEFLSHDNQKCDEDKHHTTDSASWIRSGTLSPEIFEKSTIDSNENRR
  HNQWKNSFHPLTTRSNSIMDSFCVQQAEDCLSEKSRLNRSSVSKEVFLSLPQPNNSDWIQ
  GHTRKEMGQSLDSANTSFTAILSSPDGELVDVACEDLELYVSRNNDMLTPTPDSSPRSTS
  SPSQSKNGSFTPRTANILKPLMSPPSREEIMATLLDHDLSETIYQEPFCSNPSDVPEKPR
  EIGGRLLMVETRLANDLAEFEGDFSLEGLRLWKTAFSAMTQNPRPGSPLRSGQGVVNKGS
  SNSPKMVEDKKIVIMPCKCAPSRQLVQVWLQAKEEYERSKKLPKTKPTGVVKSAENFSSS
  VNPDDKPVVPPKMDVSPCILPTTAHTKEDVDNSQIALQAPTTGCSQTASESQMLPPVASA
  SDPEKDEDDDDNYYISYSSPDSPVIPPWQQPISPDSKALNGDDRPSSPVEELPSLAFENF
  LKPIKDGIQKSPCSEPQEPLVISPINTRARTGKCESLCFHSTPIIQRKLLERLPEAPGLS
  PLSTEPKTQKLSNKKGSNTDTLRRVLLTQAKNQFAAVNTPQKETSQIDGPSLNNTYGFKV
  SIQNLQEAKALHEIQNLTLISVELHARTRRDLEPDPEFDPICALFYCISSDTPLPDTEKT
  ELTGVIVIDKDKTVFSQDIRYQTPLLIRSGITGLEVTYAADEKALFHEIANIIKRYDPDI
  LLGYEIQMHSWGYLLQRAAALSIDLCRMISRVPDDKIENRFAAERDEYGSYTMSEINIVG
  RITLNLWRIMRNEVALTNYTFENVSFHVLHQRFPLFTFRVLSDWFDNKTDLYRWKMVDHY
  VSRVRGNLQMLEQLDLIGKTSEMARLFGIQFLHVLTRGSQYRVESMMLRIAKPMNYIPVT
  PSVQQRSQMRAPQCVPLIMEPESRFYSNSVLVLDFQSLYPSIVIAYNYCFSTCLGHVENL
  GKYDEFKFGCTSLRVPPDLLYQVRHDITVSPNGVAFVKPSVRKGVLPRMLEEILKTRFMV
  KQSMKAYKQDRALSRMLDARQLGLKLIANVTFGYTSANFSGRMPCIEVGDSIVHKARETL
  ERAIKLVNDTKKWGARVVYGDTDSMFVLLKGATKEQSFKIGQEIAEAVTATNPKPVKLKF
  EKVYLPCVLQTKKRYVGYMYETLDQKDPVFDAKGIETVRRDSCPAVSKILERSLKLLFET
  RDISLIKQYVQRQCMKLLEGKASIQDFIFAKEYRGSFSYKPGACVPALELTRKMLTYDRR
  SEPQVGERVPYVIIYGTPGVPLIQLVRRPVEVLQDPTLRLNATYYITKQILPPLARIFSL
  IGIDVFSWYHELPRIHKATSSSRSEPEGRKGTISQYFTTLHCPVCDDLTQHGICSKCRSQ
  PQHVAVILNQEIRELERQQEQLVKICKNCTGCFDRHIPCVSLNCPVLFKLSRVNRELSKA
  PYLRQLLDQF
• Function: Catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (TLS). Lacks an intrinsic 3'-5' exonuclease activity and thus has no proofreading function.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Translesion synthesis by POLK (R-HSA-5655862)
  Translesion synthesis by POLI (R-HSA-5656121)
  Translesion synthesis by REV1 (R-HSA-110312)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Definitive	Altered Expression	[1]
Glioma	DIS5RPEH	Definitive	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[6]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Posttranslational Modification	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[11]
Bone osteosarcoma	DIST1004	moderate	Genetic Variation	[12]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[1]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[1]
Fanconi anemia complementation group D2	DISC76W3	moderate	Biomarker	[13]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[11]
Osteosarcoma	DISLQ7E2	moderate	Genetic Variation	[12]
Mobius syndrome	DIS9YXP5	Supportive	Autosomal dominant	[14]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[5]
Mesothelioma	DISKWK9M	Limited	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[16]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[17]
Psoriatic arthritis	DISLWTG2	Limited	Genetic Variation	[18]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[19]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	DNA polymerase zeta catalytic subunit (REV3L) affects the response to substance of Doxorubicin.	[35]
Vinblastine	DM5TVS3	Approved	DNA polymerase zeta catalytic subunit (REV3L) affects the response to substance of Vinblastine.	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DNA polymerase zeta catalytic subunit (REV3L).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[23]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase zeta catalytic subunit (REV3L).	[25]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[26]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA polymerase zeta catalytic subunit (REV3L).	[25]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[27]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[28]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[22]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA polymerase zeta catalytic subunit (REV3L).	[34]

References

• [1] Human REV3 DNA Polymerase Zeta Localizes to Mitochondria and Protects the Mitochondrial Genome.PLoS One. 2015 Oct 13;10(10):e0140409. doi: 10.1371/journal.pone.0140409. eCollection 2015.
• [2] REV3L confers chemoresistance to cisplatin in human gliomas: the potential of its RNAi for synergistic therapy.Neuro Oncol. 2009 Dec;11(6):790-802. doi: 10.1215/15228517-2009-015.
• [3] REV3L, a promising target in regulating the chemosensitivity of cervical cancer cells.PLoS One. 2015 Mar 17;10(3):e0120334. doi: 10.1371/journal.pone.0120334. eCollection 2015.
• [4] Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta.Oncogene. 2008 Oct 16;27(47):6093-101. doi: 10.1038/onc.2008.212. Epub 2008 Jul 14.
• [5] MicroRNA-340 inhibits the proliferation and promotes the apoptosis of colon cancer cells by modulating REV3L.Oncotarget. 2017 Dec 26;9(4):5155-5168. doi: 10.18632/oncotarget.23703. eCollection 2018 Jan 12.
• [6] The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer.Eur J Hum Genet. 2016 Oct;24(10):1501-5. doi: 10.1038/ejhg.2016.44. Epub 2016 May 11.
• [7] miR-145 Regulates the sensitivity of esophageal squamous cell carcinoma cells to 5-FU via targeting REV3L.Pathol Res Pract. 2019 Jul;215(7):152427. doi: 10.1016/j.prp.2019.04.019. Epub 2019 Apr 28.
• [8] Response of human REV3 gene to gastric cancer inducing carcinogen N-methyl-N'-nitro-N-nitrosoguanidine and its role in mutagenesis.World J Gastroenterol. 2003 May;9(5):888-93. doi: 10.3748/wjg.v9.i5.888.
• [9] Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck.Sci Rep. 2016 Jan 21;6:19552. doi: 10.1038/srep19552.
• [10] Absence of REV3L promotes p53-regulated cancer cell metabolism in cisplatin-treated lung carcinoma cells.Biochem Biophys Res Commun. 2018 Jan 29;496(1):199-204. doi: 10.1016/j.bbrc.2018.01.026. Epub 2018 Jan 4.
• [11] c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma.Brain. 2015 Dec;138(Pt 12):3654-72. doi: 10.1093/brain/awv287. Epub 2015 Oct 8.
• [12] Translesion polymerase genes polymorphisms and haplotypes influence survival of osteosarcoma patients.OMICS. 2015 Mar;19(3):180-5. doi: 10.1089/omi.2014.0159.
• [13] Rev3, the catalytic subunit of Pol, is required for maintaining fragile site stability in human cells.Nucleic Acids Res. 2013 Feb 1;41(4):2328-39. doi: 10.1093/nar/gks1442. Epub 2013 Jan 8.
• [14] De novo mutations in PLXND1 and REV3L cause M?bius syndrome. Nat Commun. 2015 Jun 12;6:7199. doi: 10.1038/ncomms8199.
• [15] Inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells.Neoplasia. 2011 Oct;13(10):961-70. doi: 10.1593/neo.11828.
• [16] Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes.Sci Rep. 2017 Jul 20;7(1):6037. doi: 10.1038/s41598-017-06158-3.
• [17] Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.Nat Commun. 2015 Apr 23;6:6916. doi: 10.1038/ncomms7916.
• [18] Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis.Ann Rheum Dis. 2019 Mar;78(3):e214158. doi: 10.1136/annrheumdis-2018-214158. Epub 2018 Dec 14.
• [19] Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans.Mol Med. 2014 Aug 14;20(1):341-9. doi: 10.2119/molmed.2014.00097.
• [20] 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.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [23] 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.
• [24] 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.
• [25] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [27] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [28] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [29] [Changes of nuclear matrix proteins during apoptosis of human osteosarcoma MG-63 cells induced by curcumin]. Fen Zi Xi Bao Sheng Wu Xue Bao. 2008 Dec;41(6):473-81.
• [30] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [35] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.