Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBHK0E6)

• DOT Name: DNA polymerase theta (POLQ)
• Synonyms: DNA polymerase eta
• Gene Name: POLQ
• Related Disease:
  Cockayne syndrome type 1
  Herpes simplex infection
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Nijmegen breakage syndrome
  Pancreatic cancer
  Skin cancer
  Skin neoplasm
  Thyroid gland papillary carcinoma
  Xeroderma pigmentosum
  Advanced cancer
  Breast neoplasm
  Carcinoid tumor
  Hereditary breast carcinoma
  Xeroderma pigmentosum variant type
  Colorectal carcinoma
  Cutaneous squamous cell carcinoma
• UniProt ID: DPOLQ_HUMAN
• PDB ID: 4X0P; 4X0Q; 5A9F; 5A9J; 5AGA; 6XBU; 7ZUS; 7ZX0; 7ZX1; 8E23; 8E24
• EC Number: 2.7.7.49; 2.7.7.7; 3.6.4.12
• Pfam ID: PF00270 ; PF00476 ; PF00271 ; PF20470 ; PF21099
• Sequence:
  MNLLRRSGKRRRSESGSDSFSGSGGDSSASPQFLSGSVLSPPPGLGRCLKAAAAGECKPT
  VPDYERDKLLLANWGLPKAVLEKYHSFGVKKMFEWQAECLLLGQVLEGKNLVYSAPTSAG
  KTLVAELLILKRVLEMRKKALFILPFVSVAKEKKYYLQSLFQEVGIKVDGYMGSTSPSRH
  FSSLDIAVCTIERANGLINRLIEENKMDLLGMVVVDELHMLGDSHRGYLLELLLTKICYI
  TRKSASCQADLASSLSNAVQIVGMSATLPNLELVASWLNAELYHTDFRPVPLLESVKVGN
  SIYDSSMKLVREFEPMLQVKGDEDHVVSLCYETICDNHSVLLFCPSKKWCEKLADIIARE
  FYNLHHQAEGLVKPSECPPVILEQKELLEVMDQLRRLPSGLDSVLQKTVPWGVAFHHAGL
  TFEERDIIEGAFRQGLIRVLAATSTLSSGVNLPARRVIIRTPIFGGRPLDILTYKQMVGR
  AGRKGVDTVGESILICKNSEKSKGIALLQGSLKPVRSCLQRREGEEVTGSMIRAILEIIV
  GGVASTSQDMHTYAACTFLAASMKEGKQGIQRNQESVQLGAIEACVMWLLENEFIQSTEA
  SDGTEGKVYHPTHLGSATLSSSLSPADTLDIFADLQRAMKGFVLENDLHILYLVTPMFED
  WTTIDWYRFFCLWEKLPTSMKRVAELVGVEEGFLARCVKGKVVARTERQHRQMAIHKRFF
  TSLVLLDLISEVPLREINQKYGCNRGQIQSLQQSAAVYAGMITVFSNRLGWHNMELLLSQ
  FQKRLTFGIQRELCDLVRVSLLNAQRARVLYASGFHTVADLARANIVEVEVILKNAVPFK
  SARKAVDEEEEAVEERRNMRTIWVTGRKGLTEREAAALIVEEARMILQQDLVEMGVQWNP
  CALLHSSTCSLTHSESEVKEHTFISQTKSSYKKLTSKNKSNTIFSDSYIKHSPNIVQDLN
  KSREHTSSFNCNFQNGNQEHQTCSIFRARKRASLDINKEKPGASQNEGKTSDKKVVQTFS
  QKTKKAPLNFNSEKMSRSFRSWKRRKHLKRSRDSSPLKDSGACRIHLQGQTLSNPSLCED
  PFTLDEKKTEFRNSGPFAKNVSLSGKEKDNKTSFPLQIKQNCSWNITLTNDNFVEHIVTG
  SQSKNVTCQATSVVSEKGRGVAVEAEKINEVLIQNGSKNQNVYMKHHDIHPINQYLRKQS
  HEQTSTITKQKNIIERQMPCEAVSSYINRDSNVTINCERIKLNTEENKPSHFQALGDDIS
  RTVIPSEVLPSAGAFSKSEGQHENFLNISRLQEKTGTYTTNKTKNNHVSDLGLVLCDFED
  SFYLDTQSEKIIQQMATENAKLGAKDTNLAAGIMQKSLVQQNSMNSFQKECHIPFPAEQH
  PLGATKIDHLDLKTVGTMKQSSDSHGVDILTPESPIFHSPILLEENGLFLKKNEVSVTDS
  QLNSFLQGYQTQETVKPVILLIPQKRTPTGVEGECLPVPETSLNMSDSLLFDSFSDDYLV
  KEQLPDMQMKEPLPSEVTSNHFSDSLCLQEDLIKKSNVNENQDTHQQLTCSNDESIIFSE
  MDSVQMVEALDNVDIFPVQEKNHTVVSPRALELSDPVLDEHHQGDQDGGDQDERAEKSKL
  TGTRQNHSFIWSGASFDLSPGLQRILDKVSSPLENEKLKSMTINFSSLNRKNTELNEEQE
  VISNLETKQVQGISFSSNNEVKSKIEMLENNANHDETSSLLPRKESNIVDDNGLIPPTPI
  PTSASKLTFPGILETPVNPWKTNNVLQPGESYLFGSPSDIKNHDLSPGSRNGFKDNSPIS
  DTSFSLQLSQDGLQLTPASSSSESLSIIDVASDQNLFQTFIKEWRCKKRFSISLACEKIR
  SLTSSKTATIGSRFKQASSPQEIPIRDDGFPIKGCDDTLVVGLAVCWGGRDAYYFSLQKE
  QKHSEISASLVPPSLDPSLTLKDRMWYLQSCLRKESDKECSVVIYDFIQSYKILLLSCGI
  SLEQSYEDPKVACWLLDPDSQEPTLHSIVTSFLPHELPLLEGMETSQGIQSLGLNAGSEH
  SGRYRASVESILIFNSMNQLNSLLQKENLQDVFRKVEMPSQYCLALLELNGIGFSTAECE
  SQKHIMQAKLDAIETQAYQLAGHSFSFTSSDDIAEVLFLELKLPPNREMKNQGSKKTLGS
  TRRGIDNGRKLRLGRQFSTSKDVLNKLKALHPLPGLILEWRRITNAITKVVFPLQREKCL
  NPFLGMERIYPVSQSHTATGRITFTEPNIQNVPRDFEIKMPTLVGESPPSQAVGKGLLPM
  GRGKYKKGFSVNPRCQAQMEERAADRGMPFSISMRHAFVPFPGGSILAADYSQLELRILA
  HLSHDRRLIQVLNTGADVFRSIAAEWKMIEPESVGDDLRQQAKQICYGIIYGMGAKSLGE
  QMGIKENDAACYIDSFKSRYTGINQFMTETVKNCKRDGFVQTILGRRRYLPGIKDNNPYR
  KAHAERQAINTIVQGSAADIVKIATVNIQKQLETFHSTFKSHGHREGMLQSDQTGLSRKR
  KLQGMFCPIRGGFFILQLHDELLYEVAEEDVVQVAQIVKNEMESAVKLSVKLKVKVKIGA
  SWGELKDFDV
• Function: Low-fidelity DNA polymerase with a helicase activity that promotes microhomology-mediated end-joining (MMEJ), an alternative non-homologous end-joining (NHEJ) machinery required to repair double-strand breaks in DNA during mitosis. MMEJ is an error-prone repair pathway that produces deletions of sequences from the strand being repaired and promotes genomic rearrangements, such as telomere fusions, some of them leading to cellular transformation. MMEJ is required during mitosis to repair persistent double-strand breaks that originate in S-phase. Although error-prone, MMEJ protects against chromosomal instability and tumorigenesis. The polymerase acts by binding directly the 2 ends of resected double-strand breaks, allowing microhomologous sequences in the overhangs to form base pairs. It then extends each strand from the base-paired region using the opposing overhang as a template. Requires partially resected DNA containing 2 to 6 base pairs of microhomology to perform MMEJ. The polymerase lacks proofreading activity and is highly promiscuous: unlike most polymerases, promotes extension of ssDNA and partial ssDNA (pssDNA) substrates. When the ends of a break do not contain terminal microhomology must identify embedded complementary sequences through a scanning step. Also shows endonuclease activity, which is required to trim the 3' ends before synthesis can occur, thereby preventing non-paired tails. Also acts as a DNA helicase, promoting dissociation of the replication protein A complex (RPA/RP-A), composed of RPA1, RPA2 and RPA3, from resected double-strand breaks to allow their annealing and subsequent joining by MMEJ. Removal of RPA/RP-A complex proteins prevents RAD51 accumulation at resected ends, thereby inhibiting homology-recombination repair (HR) pathway. Also shows RNA-directed DNA polymerase activity to mediate DNA repair in vitro; however this activity needs additional evidence in vivo. May also have lyase activity. Involved in somatic hypermutation of immunoglobulin genes, a process that requires the activity of DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs. POLQ-mediated end joining activity is involved in random integration of exogenous DNA hampers.
• Tissue Specificity: Highly expressed in testis.
• Reactome Pathway: HDR through MMEJ (alt-NHEJ) (R-HSA-5685939)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cockayne syndrome type 1	DIS9JFVY	Definitive	Biomarker	[1]
Herpes simplex infection	DISL1SAV	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[5]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[6]
Skin cancer	DISTM18U	Strong	Biomarker	[7]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[8]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[9]
Xeroderma pigmentosum	DISQ9H19	Strong	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[2]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[10]
Carcinoid tumor	DISMNRDC	moderate	Genetic Variation	[11]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[10]
Xeroderma pigmentosum variant type	DISNPX76	moderate	Genetic Variation	[12]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[13]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA polymerase theta (POLQ).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase theta (POLQ).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA polymerase theta (POLQ).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA polymerase theta (POLQ).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA polymerase theta (POLQ).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA polymerase theta (POLQ).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA polymerase theta (POLQ).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA polymerase theta (POLQ).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA polymerase theta (POLQ).	[22]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of DNA polymerase theta (POLQ).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase theta (POLQ).	[24]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of DNA polymerase theta (POLQ).	[25]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA polymerase theta (POLQ).	[26]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA polymerase theta (POLQ).	[24]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA polymerase theta (POLQ).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA polymerase theta (POLQ).	[28]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA polymerase theta (POLQ).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA polymerase theta (POLQ).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA polymerase theta (POLQ).	[31]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA polymerase theta (POLQ).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA polymerase theta (POLQ).	[33]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA polymerase theta (POLQ).	[34]

References

• [1] Contributions of nucleotide excision repair, DNA polymerase eta, and homologous recombination to replication of UV-irradiated herpes simplex virus type 1.J Biol Chem. 2010 Apr 30;285(18):13761-8. doi: 10.1074/jbc.M110.107920. Epub 2010 Mar 9.
• [2] DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse.J Biol Chem. 2019 Mar 15;294(11):3909-3919. doi: 10.1074/jbc.RA118.005188. Epub 2019 Jan 17.
• [3] BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese.Int J Cancer. 2020 Feb 15;146(4):1042-1051. doi: 10.1002/ijc.32619. Epub 2019 Aug 26.
• [4] POLQ Overexpression Is Associated with an Increased Somatic Mutation Load and PLK4 Overexpression in Lung Adenocarcinoma.Cancers (Basel). 2019 May 24;11(5):722. doi: 10.3390/cancers11050722.
• [5] Parkin regulates translesion DNA synthesis in response to UV radiation.Oncotarget. 2017 May 30;8(22):36423-36437. doi: 10.18632/oncotarget.16855.
• [6] Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers.Cancer Res. 2008 Feb 15;68(4):971-5. doi: 10.1158/0008-5472.CAN-07-6272.
• [7] Error-Prone Replication through UV Lesions by DNA Polymerase Protects against Skin Cancers.Cell. 2019 Mar 7;176(6):1295-1309.e15. doi: 10.1016/j.cell.2019.01.023. Epub 2019 Feb 14.
• [8] Differential Roles of Rad18 and Chk2 in Genome Maintenance and Skin Carcinogenesis Following UV Exposure.J Invest Dermatol. 2018 Dec;138(12):2550-2557. doi: 10.1016/j.jid.2018.05.015. Epub 2018 May 31.
• [9] Immune cell infiltrate-associated dysregulation of DNA repair machinery may predispose to papillary thyroid carcinogenesis.Surgery. 2020 Jan;167(1):66-72. doi: 10.1016/j.surg.2019.02.024. Epub 2019 Aug 19.
• [10] A DNA repair variant in POLQ (c.-1060A > G) is associated to hereditary breast cancer patients: a case-control study.BMC Cancer. 2014 Nov 19;14:850. doi: 10.1186/1471-2407-14-850.
• [11] Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D.J Pathol. 2017 Mar;241(4):488-500. doi: 10.1002/path.4853. Epub 2016 Dec 29.
• [12] Molecular analysis of DNA polymerase eta gene in Japanese patients diagnosed as xeroderma pigmentosum variant type.J Invest Dermatol. 2007 Jul;127(7):1745-51. doi: 10.1038/sj.jid.5700759. Epub 2007 Mar 8.
• [13] 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.
• [14] Mutations in DNA polymerase eta are not detected in squamous cell carcinoma of the skin.Int J Cancer. 2006 Nov 1;119(9):2225-7. doi: 10.1002/ijc.22099.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [18] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [21] 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.
• [22] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [27] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [30] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.