Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN07WXU)

• DOT Name: DNA polymerase eta (POLH)
• Synonyms: EC 2.7.7.7; RAD30 homolog A; Xeroderma pigmentosum variant type protein
• Gene Name: POLH
• Related Disease:
  Cockayne syndrome type 1
  Herpes simplex infection
  Xeroderma pigmentosum variant type
  Advanced cancer
  Neoplasm
  Nijmegen breakage syndrome
  Psoriatic arthritis
  Serous cystadenocarcinoma
  Skin cancer
  Skin neoplasm
  Squamous cell carcinoma
  Xeroderma pigmentosum
  Xeroderma pigmentosum group A
  Xeroderma pigmentosum group C
  Xeroderma pigmentosum group G
  Colorectal carcinoma
  Cutaneous squamous cell carcinoma
  Hereditary breast carcinoma
  Metastatic malignant neoplasm
  Carcinoma
• UniProt ID: POLH_HUMAN
• PDB ID: 2I5O ; 2LSK ; 3JAA ; 3MR2 ; 3MR3 ; 3MR5 ; 3MR6 ; 3SI8 ; 3TQ1 ; 3WUP ; 4DL2 ; 4DL3 ; 4DL4 ; 4DL5 ; 4DL6 ; 4DL7 ; 4ECQ ; 4ECR ; 4ECS ; 4ECT ; 4ECU ; 4ECV ; 4ECW ; 4ECX ; 4ECY ; 4ECZ ; 4ED0 ; 4ED1 ; 4ED2 ; 4ED3 ; 4ED6 ; 4ED7 ; 4ED8 ; 4EEY ; 4J9K ; 4J9L ; 4J9M ; 4J9N ; 4J9O ; 4J9P ; 4J9Q ; 4J9R ; 4J9S ; 4O3N ; 4O3O ; 4O3P ; 4O3Q ; 4O3R ; 4O3S ; 4Q8E ; 4Q8F ; 4RNM ; 4RNN ; 4RNO ; 4RU9 ; 4YP3 ; 4YQW ; 4YR0 ; 4YR2 ; 4YR3 ; 5DG7 ; 5DG8 ; 5DG9 ; 5DGA ; 5DGB ; 5DLF ; 5DLG ; 5DQG ; 5DQH ; 5DQI ; 5EWE ; 5EWF ; 5EWG ; 5F9L ; 5F9N ; 5JUM ; 5KFA ; 5KFB ; 5KFC ; 5KFD ; 5KFE ; 5KFF ; 5KFG ; 5KFH ; 5KFI ; 5KFJ ; 5KFK ; 5KFL ; 5KFM ; 5KFN ; 5KFO ; 5KFP ; 5KFQ ; 5KFR ; 5KFS ; 5KFT ; 5KFU ; 5KFV ; 5KFW ; 5KFX ; 5KFY ; 5KFZ ; 5KG0 ; 5KG1 ; 5KG2 ; 5KG3 ; 5KG4 ; 5KG5 ; 5KG6 ; 5KG7 ; 5L1I ; 5L1J ; 5L1K ; 5L1L ; 5L9X ; 6D0M ; 6D0Z ; 6M7O ; 6M7P ; 6M7T ; 6M7U ; 6M7V ; 6MP3 ; 6MQ8 ; 6MXO ; 6PL7 ; 6PL8 ; 6PLC ; 6PZ3 ; 6Q02 ; 6UI2 ; 6UQI ; 6V5K ; 6W5X ; 6WK6 ; 7L69 ; 7LCD ; 7M7L ; 7M7M ; 7M7N ; 7M7O ; 7M7P ; 7M7Q ; 7M7R ; 7M7S ; 7M7T ; 7M7U ; 7M7Y ; 7M7Z ; 7M80 ; 7M81 ; 7M82 ; 7M83 ; 7M84 ; 7M85 ; 7M86 ; 7M87 ; 7M88 ; 7M89 ; 7M8A ; 7M8B ; 7M8C ; 7M8D ; 7U72 ; 7U73 ; 7U74 ; 7U75 ; 7U76 ; 7U77 ; 7U78 ; 7U79 ; 7U7A ; 7U7B ; 7U7C ; 7U7D ; 7U7E ; 7U7F ; 7U7G ; 7U7I ; 7U7J ; 7U7K ; 7U7L ; 7U7R ; 7U7S ; 7U7T ; 7U7U ; 7U7V ; 7U7W ; 7U7X ; 7U7Y ; 7U7Z ; 7U80 ; 7U81 ; 7U82 ; 7U83 ; 7U84 ; 8E85 ; 8E86 ; 8E87 ; 8E88 ; 8E89 ; 8E8A ; 8E8B ; 8E8C ; 8E8D ; 8E8E ; 8E8F ; 8E8G ; 8E8H ; 8E8J ; 8E8K ; 8EVE ; 8EVF ; 8FN3 ; 8FOG ; 8GKR ; 8GML ; 8SKI
• EC Number: 2.7.7.7
• Pfam ID: PF00817 ; PF11799 ; PF21704 ; PF18439
• Sequence:
  MATGQDRVVALVDMDCFFVQVEQRQNPHLRNKPCAVVQYKSWKGGGIIAVSYEARAFGVT
  RSMWADDAKKLCPDLLLAQVRESRGKANLTKYREASVEVMEIMSRFAVIERASIDEAYVD
  LTSAVQERLQKLQGQPISADLLPSTYIEGLPQGPTTAEETVQKEGMRKQGLFQWLDSLQI
  DNLTSPDLQLTVGAVIVEEMRAAIERETGFQCSAGISHNKVLAKLACGLNKPNRQTLVSH
  GSVPQLFSQMPIRKIRSLGGKLGASVIEILGIEYMGELTQFTESQLQSHFGEKNGSWLYA
  MCRGIEHDPVKPRQLPKTIGCSKNFPGKTALATREQVQWWLLQLAQELEERLTKDRNDND
  RVATQLVVSIRVQGDKRLSSLRRCCALTRYDAHKMSHDAFTVIKNCNTSGIQTEWSPPLT
  MLFLCATKFSASAPSSSTDITSFLSSDPSSLPKVPVTSSEAKTQGSGPAVTATKKATTSL
  ESFFQKAAERQKVKEASLSSLTAPTQAPMSNSPSKPSLPFQTSQSTGTEPFFKQKSLLLK
  QKQLNNSSVSSPQQNPWSNCKALPNSLPTEYPGCVPVCEGVSKLEESSKATPAEMDLAHN
  SQSMHASSASKSVLEVTQKATPNPSLLAAEDQVPCEKCGSLVPVWDMPEHMDYHFALELQ
  KSFLQPHSSNPQVVSAVSHQGKRNPKSPLACTNKRPRPEGMQTLESFFKPLTH
• Function: DNA polymerase specifically involved in the DNA repair by translesion synthesis (TLS). Due to low processivity on both damaged and normal DNA, cooperates with the heterotetrameric (REV3L, REV7, POLD2 and POLD3) POLZ complex for complete bypass of DNA lesions. Inserts one or 2 nucleotide(s) opposite the lesion, the primer is further extended by the tetrameric POLZ complex. In the case of 1,2-intrastrand d(GpG)-cisplatin cross-link, inserts dCTP opposite the 3' guanine. Particularly important for the repair of UV-induced pyrimidine dimers. Although inserts the correct base, may cause base transitions and transversions depending upon the context. May play a role in hypermutation at immunoglobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have any lyase activity, preventing the release of the 5'-deoxyribose phosphate (5'-dRP) residue. This covalent trapping of the enzyme by the 5'-dRP residue inhibits its DNA synthetic activity during base excision repair, thereby avoiding high incidence of mutagenesis. Targets POLI to replication foci.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Termination of translesion DNA synthesis (R-HSA-5656169)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Translesion Synthesis by POLH (R-HSA-110320)

Molecular Interaction Atlas (MIA) of This DOT

20 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]
Xeroderma pigmentosum variant type	DISNPX76	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[5]
Psoriatic arthritis	DISLWTG2	Strong	Posttranslational Modification	[6]
Serous cystadenocarcinoma	DISVK716	Strong	Biomarker	[7]
Skin cancer	DISTM18U	Strong	Biomarker	[8]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[10]
Xeroderma pigmentosum	DISQ9H19	Strong	Genetic Variation	[11]
Xeroderma pigmentosum group A	DIS38HWC	Strong	Genetic Variation	[12]
Xeroderma pigmentosum group C	DIS8DQXS	Strong	Genetic Variation	[12]
Xeroderma pigmentosum group G	DIS4PV33	Strong	Genetic Variation	[12]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[4]
Cutaneous squamous cell carcinoma	DIS3LXUG	moderate	Genetic Variation	[10]
Hereditary breast carcinoma	DISAEZT5	moderate	Biomarker	[13]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[4]
Carcinoma	DISH9F1N	Limited	Biomarker	[14]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	DNA polymerase eta (POLH) affects the response to substance of Hydroquinone.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA polymerase eta (POLH).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase eta (POLH).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA polymerase eta (POLH).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA polymerase eta (POLH).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA polymerase eta (POLH).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA polymerase eta (POLH).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA polymerase eta (POLH).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA polymerase eta (POLH).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of DNA polymerase eta (POLH).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase eta (POLH).	[23]
Marinol	DM70IK5	Approved	Marinol increases the expression of DNA polymerase eta (POLH).	[24]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of DNA polymerase eta (POLH).	[25]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA polymerase eta (POLH).	[23]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of DNA polymerase eta (POLH).	[26]
Fotemustine	DMV62ED	Approved	Fotemustine increases the expression of DNA polymerase eta (POLH).	[26]
Lomustine	DMMWSUL	Approved	Lomustine increases the expression of DNA polymerase eta (POLH).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA polymerase eta (POLH).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA polymerase eta (POLH).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA polymerase eta (POLH).	[25]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of DNA polymerase eta (POLH).	[29]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of DNA polymerase eta (POLH).	[30]
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 eta (POLH).	[31]

References

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• [8] ATR/Chk1 Pathway is Activated by Oxidative Stress in Response to UVA Light in Human Xeroderma Pigmentosum Variant Cells.Photochem Photobiol. 2019 Jan;95(1):345-354. doi: 10.1111/php.13041. Epub 2018 Nov 23.
• [9] 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.
• [10] The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin.Int J Mol Med. 2007 Apr;19(4):589-96.
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• [12] Genotype-phenotype correlation of xeroderma pigmentosum in a Chinese Han population.Br J Dermatol. 2015 Apr;172(4):1096-102. doi: 10.1111/bjd.13429. Epub 2015 Feb 27.
• [13] Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.Int J Cancer. 2019 Apr 15;144(8):1962-1974. doi: 10.1002/ijc.31921. Epub 2018 Nov 13.
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• [16] 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.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [23] 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.
• [24] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [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] Translesion polymerase is upregulated by cancer therapeutics and confers anticancer drug resistance. Cancer Res. 2014 Oct 1;74(19):5585-96. doi: 10.1158/0008-5472.CAN-14-0953. Epub 2014 Aug 14.
• [27] 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.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013 Apr 16;8(4):e61980. doi: 10.1371/journal.pone.0061980. Print 2013.
• [30] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [31] 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.
• [32] Down-regulation of Pol expression leads to increased DNA damage, apoptosis and enhanced S phase arrest in L-02 cells exposed to hydroquinone. Toxicol Lett. 2012 Oct 17;214(2):209-17. doi: 10.1016/j.toxlet.2012.08.025. Epub 2012 Sep 5.