Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ24QGM)

• DOT Name: DNA polymerase lambda (POLL)
• Synonyms: Pol Lambda; EC 2.7.7.7; EC 4.2.99.-; DNA polymerase beta-2; Pol beta2; DNA polymerase kappa
• Gene Name: POLL
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Chromosomal disorder
  Glioblastoma multiforme
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Lung cancer
  Lung neoplasm
  Male infertility
  Primary ciliary dyskinesia
  Prostate cancer
  Prostate carcinoma
  Lung carcinoma
  Werner syndrome
  Colorectal carcinoma
• UniProt ID: DPOLL_HUMAN
• PDB ID: 1NZP ; 1RZT ; 1XSL ; 1XSN ; 1XSP ; 2BCQ ; 2BCR ; 2BCS ; 2BCU ; 2BCV ; 2GWS ; 2JW5 ; 2PFN ; 2PFO ; 2PFP ; 2PFQ ; 3C5F ; 3C5G ; 3HW8 ; 3HWT ; 3HX0 ; 3MDA ; 3MDC ; 3MGH ; 3MGI ; 3PML ; 3PMN ; 3PNC ; 3UPQ ; 3UQ0 ; 3UQ2 ; 4FO6 ; 4K4G ; 4K4H ; 4K4I ; 4X5V ; 4XA5 ; 4XQ8 ; 4XRH ; 4XUS ; 5CA7 ; 5CB1 ; 5CHG ; 5CJ7 ; 5CP2 ; 5CR0 ; 5CWR ; 5DDM ; 5DDY ; 5DKW ; 5III ; 5IIJ ; 5IIK ; 5IIL ; 5IIM ; 5IIN ; 5IIO ; 5W4G ; 7M07 ; 7M08 ; 7M09 ; 7M0A ; 7M0B ; 7M0C ; 7M0D ; 7M0E ; 7M43 ; 7M44 ; 7M45 ; 7M46 ; 7M47 ; 7M48 ; 7M49 ; 7M4A ; 7M4B ; 7M4C ; 7M4D ; 7M4E ; 7M4F ; 7M4G ; 7M4H ; 7M4I ; 7M4J ; 7M4K ; 7M4L ; 7UN7
• EC Number: 2.7.7.7; 4.2.99.-
• Pfam ID: PF14792 ; PF14791 ; PF10391 ; PF14716
• Sequence:
  MDPRGILKAFPKRQKIHADASSKVLAKIPRREEGEEAEEWLSSLRAHVVRTGIGRARAEL
  FEKQIVQHGGQLCPAQGPGVTHIVVDEGMDYERALRLLRLPQLPPGAQLVKSAWLSLCLQ
  ERRLVDVAGFSIFIPSRYLDHPQPSKAEQDASIPPGTHEALLQTALSPPPPPTRPVSPPQ
  KAKEAPNTQAQPISDDEASDGEETQVSAADLEALISGHYPTSLEGDCEPSPAPAVLDKWV
  CAQPSSQKATNHNLHITEKLEVLAKAYSVQGDKWRALGYAKAINALKSFHKPVTSYQEAC
  SIPGIGKRMAEKIIEILESGHLRKLDHISESVPVLELFSNIWGAGTKTAQMWYQQGFRSL
  EDIRSQASLTTQQAIGLKHYSDFLERMPREEATEIEQTVQKAAQAFNSGLLCVACGSYRR
  GKATCGDVDVLITHPDGRSHRGIFSRLLDSLRQEGFLTDDLVSQEENGQQQKYLGVCRLP
  GPGRRHRRLDIIVVPYSEFACALLYFTGSAHFNRSMRALAKTKGMSLSEHALSTAVVRNT
  HGCKVGPGRVLPTPTEKDVFRLLGLPYREPAERDW
• Function: DNA polymerase that functions in several pathways of DNA repair. Involved in base excision repair (BER) responsible for repair of lesions that give rise to abasic (AP) sites in DNA. Also contributes to DNA double-strand break repair by non-homologous end joining and homologous recombination. Has both template-dependent and template-independent (terminal transferase) DNA polymerase activities. Has also a 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity.
• Tissue Specificity: Expressed in a number of tissues. Abundant in testis.
• KEGG Pathway:
  Base excision repair (hsa03410)
  Non-homologous end-joining (hsa03450)
• Reactome Pathway: Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[8]
Male infertility	DISY3YZZ	Strong	Biomarker	[9]
Primary ciliary dyskinesia	DISOBC7V	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[10]
Werner syndrome	DISZY45W	moderate	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]

7 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 polymerase lambda (POLL).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA polymerase lambda (POLL).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of DNA polymerase lambda (POLL).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of DNA polymerase lambda (POLL).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA polymerase lambda (POLL).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of DNA polymerase lambda (POLL).	[19]
HONOKIOL	DMJWT3X	Investigative	HONOKIOL decreases the activity of DNA polymerase lambda (POLL).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of DNA polymerase lambda (POLL).	[18]

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] Hypothesis driven single nucleotide polymorphism search (HyDn-SNP-S).DNA Repair (Amst). 2013 Sep;12(9):733-40. doi: 10.1016/j.dnarep.2013.06.001. Epub 2013 Jul 5.
• [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] 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.
• [5] 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.
• [6] 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.
• [7] Cloning, expression and characterization of human tissue-specific DNA polymerase lambda2.Sci China C Life Sci. 2007 Aug;50(4):457-65. doi: 10.1007/s11427-007-0059-4.
• [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] Hydrocephalus, situs inversus, chronic sinusitis, and male infertility in DNA polymerase lambda-deficient mice: possible implication for the pathogenesis of immotile cilia syndrome.Mol Cell Biol. 2002 Apr;22(8):2769-76. doi: 10.1128/MCB.22.8.2769-2776.2002.
• [10] 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.
• [11] Mutations induced by 8-oxo-7,8-dihydroguanine in WRN- and DNA polymerase -double knockdown cells.Mutagenesis. 2018 Oct 11;33(4):301-310. doi: 10.1093/mutage/gey024.
• [12] Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase kappa in colorectal cancer.Oncogene. 2007 May 17;26(23):3387-94. doi: 10.1038/sj.onc.1210116. Epub 2006 Nov 13.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations. Nucleic Acids Res. 2016 Dec 15;44(22):10727-10743. doi: 10.1093/nar/gkw873. Epub 2016 Sep 30.
• [18] 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.
• [19] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [20] Honokiol Inhibits DNA Polymerases and and Increases Bleomycin Sensitivity of Human Cancer Cells. Chem Res Toxicol. 2017 Feb 20;30(2):715-725. doi: 10.1021/acs.chemrestox.6b00451. Epub 2017 Jan 19.