Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKZ38JH)

• DOT Name: DNA polymerase kappa (POLK)
• Synonyms: EC 2.7.7.7; DINB protein; DINP
• Gene Name: POLK
• Related Disease:
  Adult glioblastoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cardiac failure
  Chromosomal disorder
  Hepatitis B virus infection
  Lung cancer
  Non-small-cell lung cancer
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Prostate cancer
  Stroke
  Type-1/2 diabetes
  Lung carcinoma
  Metastatic malignant neoplasm
  Colorectal carcinoma
  Glioblastoma multiforme
  Neoplasm
  Prostate neoplasm
• UniProt ID: POLK_HUMAN
• PDB ID: 1T94; 2LSI; 2OH2; 2W7O; 2W7P; 3IN5; 3PZP; 4BA9; 4GK5; 4U6P; 4U7C; 5T14; 5W2A; 5W2C; 6BRX; 6BS1; 6CST; 7NV0; 7NV1
• EC Number: 2.7.7.7
• Pfam ID: PF00817 ; PF11799 ; PF11798
• Sequence:
  MDSTKEKCDSYKDDLLLRMGLNDNKAGMEGLDKEKINKIIMEATKGSRFYGNELKKEKQV
  NQRIENMMQQKAQITSQQLRKAQLQVDRFAMELEQSRNLSNTIVHIDMDAFYAAVEMRDN
  PELKDKPIAVGSMSMLSTSNYHARRFGVRAAMPGFIAKRLCPQLIIVPPNFDKYRAVSKE
  VKEILADYDPNFMAMSLDEAYLNITKHLEERQNWPEDKRRYFIKMGSSVENDNPGKEVNK
  LSEHERSISPLLFEESPSDVQPPGDPFQVNFEEQNNPQILQNSVVFGTSAQEVVKEIRFR
  IEQKTTLTASAGIAPNTMLAKVCSDKNKPNGQYQILPNRQAVMDFIKDLPIRKVSGIGKV
  TEKMLKALGIITCTELYQQRALLSLLFSETSWHYFLHISLGLGSTHLTRDGERKSMSVER
  TFSEINKAEEQYSLCQELCSELAQDLQKERLKGRTVTIKLKNVNFEVKTRASTVSSVVST
  AEEIFAIAKELLKTEIDADFPHPLRLRLMGVRISSFPNEEDRKHQQRSIIGFLQAGNQAL
  SATECTLEKTDKDKFVKPLEMSHKKSFFDKKRSERKWSHQDTFKCEAVNKQSFQTSQPFQ
  VLKKKMNENLEISENSDDCQILTCPVCFRAQGCISLEALNKHVDECLDGPSISENFKMFS
  CSHVSATKVNKKENVPASSLCEKQDYEAHPKIKEISSVDCIALVDTIDNSSKAESIDALS
  NKHSKEECSSLPSKSFNIEHCHQNSSSTVSLENEDVGSFRQEYRQPYLCEVKTGQALVCP
  VCNVEQKTSDLTLFNVHVDVCLNKSFIQELRKDKFNPVNQPKESSRSTGSSSGVQKAVTR
  TKRPGLMTKYSTSKKIKPNNPKHTLDIFFK
• Function: DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity.
• Tissue Specificity: Detected at low levels in testis, spleen, prostate and ovary. Detected at very low levels in kidney, colon, brain, heart, liver, lung, placenta, pancreas and peripheral blood leukocytes.
• KEGG Pathway:
  Fanconi anemia pathway (hsa03460)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Thyroid cancer (hsa05216)
  Basal cell carcinoma (hsa05217)
  Melanoma (hsa05218)
  Chronic myeloid leukemia (hsa05220)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Termination of translesion DNA synthesis (R-HSA-5656169)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Gap-filling DNA repair synthesis and ligation in GG-NER (R-HSA-5696397)
  Dual Incision in GG-NER (R-HSA-5696400)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Translesion synthesis by POLK (R-HSA-5655862)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Cardiac failure	DISDC067	Strong	Genetic Variation	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[9]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Stroke	DISX6UHX	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[4]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[11]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[12]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA polymerase kappa (POLK).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA polymerase kappa (POLK).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA polymerase kappa (POLK).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA polymerase kappa (POLK).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of DNA polymerase kappa (POLK).	[17]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of DNA polymerase kappa (POLK).	[18]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of DNA polymerase kappa (POLK).	[19]
Guanine	DMIWLJE	Phase 3	Guanine decreases the activity of DNA polymerase kappa (POLK).	[20]
MK-886	DMT0O7H	Discontinued in Phase 2	MK-886 decreases the activity of DNA polymerase kappa (POLK).	[22]
680C91	DMCDTIG	Preclinical	680C91 decreases the expression of DNA polymerase kappa (POLK).	[23]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE affects the activity of DNA polymerase kappa (POLK).	[24]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of DNA polymerase kappa (POLK).	[23]

1 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 increases the sumoylation of DNA polymerase kappa (POLK).	[21]

References

• [1] Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms.ACS Chem Biol. 2019 Jun 21;14(6):1337-1351. doi: 10.1021/acschembio.9b00304. Epub 2019 May 22.
• [2] Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma.Fam Cancer. 2019 Jan;18(1):113-119. doi: 10.1007/s10689-018-0099-x.
• [3] Association Between Single Nucleotide Polymorphisms in DNA Polymerase Kappa Gene and Breast Cancer Risk in Chinese Han Population: A STROBE-Compliant Observational Study.Medicine (Baltimore). 2016 Jan;95(2):e2466. doi: 10.1097/MD.0000000000002466.
• [4] Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.Front Genet. 2016 Oct 13;7:179. doi: 10.3389/fgene.2016.00179. eCollection 2016.
• [5] The absence of Mth1 inactivation and DNA polymerase kappa overexpression in rat mammary carcinomas with frequent A:T to C:G transversions.Jpn J Cancer Res. 2002 May;93(5):501-6. doi: 10.1111/j.1349-7006.2002.tb01284.x.
• [6] Effects of DNA polymerase kappa and mismatch repair on dose-responses of chromosome aberrations induced by three oxidative genotoxins in human cells.Environ Mol Mutagen. 2020 Jan;61(1):193-199. doi: 10.1002/em.22315. Epub 2019 Jul 25.
• [7] DNA Polymerase Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus.PLoS Pathog. 2016 Oct 26;12(10):e1005893. doi: 10.1371/journal.ppat.1005893. eCollection 2016 Oct.
• [8] Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis.Cancer Res. 2005 Jan 1;65(1):325-30.
• [9] Association of POLK polymorphisms with platinum-based chemotherapy response and severe toxicity in non-small cell lung cancer patients.Cell Biochem Biophys. 2014 Nov;70(2):1227-37. doi: 10.1007/s12013-014-0046-x.
• [10] Somatic Mutations in Catalytic Core of POLK Reported in Prostate Cancer Alter Translesion DNA Synthesis.Hum Mutat. 2015 Sep;36(9):873-80. doi: 10.1002/humu.22820. Epub 2015 Jun 25.
• [11] Elevated expression of DNA polymerase kappa in human lung cancer is associated with p53 inactivation: Negative regulation of POLK promoter activity by p53.Int J Oncol. 2004 Jul;25(1):161-5.
• [12] The role of double-strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression-clinicopathological data and survival.J Surg Oncol. 2020 Apr;121(5):906-916. doi: 10.1002/jso.25737. Epub 2019 Oct 25.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Leukotriene biosynthesis inhibitor MK886 impedes DNA polymerase activity. Chem Res Toxicol. 2013 Feb 18;26(2):221-32. doi: 10.1021/tx300392m. Epub 2013 Jan 31.
• [23] Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells. Chem Res Toxicol. 2016 Jan 19;29(1):101-8. doi: 10.1021/acs.chemrestox.5b00452. Epub 2015 Dec 30.
• [24] Translesional DNA synthesis through a C8-guanyl adduct of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in Vitro: REV1 inserts dC opposite the lesion, and DNA polymerase kappa potentially catalyzes extension reaction from the 3'-dC terminus. J Biol Chem. 2009 Sep 18;284(38):25585-92. doi: 10.1074/jbc.M109.037259. Epub 2009 Jul 23.