Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBA4DCE)

• DOT Name: DNA polymerase iota (POLI)
• Synonyms: EC 2.7.7.7; Eta2; RAD30 homolog B
• Gene Name: POLI
• Related Disease:
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Burkitt lymphoma
  Carcinoma of esophagus
  Chronic kidney disease
  Esophageal squamous cell carcinoma
  High blood pressure
  Lung cancer
  Lung carcinoma
  Narcolepsy
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adenocarcinoma
  Asthma
  Human papillomavirus infection
  Psoriasis
• UniProt ID: POLI_HUMAN
• PDB ID: 1T3N ; 1ZET ; 2ALZ ; 2DPI ; 2DPJ ; 2FLL ; 2FLN ; 2FLP ; 2KHU ; 2KHW ; 2KTF ; 2L0F ; 2L0G ; 2MBB ; 3EPG ; 3EPI ; 3G6V ; 3G6X ; 3G6Y ; 3GV5 ; 3GV7 ; 3GV8 ; 3H40 ; 3H4B ; 3H4D ; 3NGD ; 3OSN ; 3Q8P ; 3Q8Q ; 3Q8R ; 3Q8S ; 4EBC ; 4EBD ; 4EBE ; 4EYH ; 4EYI ; 4FS1 ; 4FS2 ; 5KT2 ; 5KT3 ; 5KT4 ; 5KT5 ; 5KT6 ; 5KT7 ; 5ULW ; 5ULX
• EC Number: 2.7.7.7
• Pfam ID: PF00817 ; PF11799
• Sequence:
  MEKLGVEPEEEGGGDDDEEDAEAWAMELADVGAAASSQGVHDQVLPTPNASSRVIVHVDL
  DCFYAQVEMISNPELKDKPLGVQQKYLVVTCNYEARKLGVKKLMNVRDAKEKCPQLVLVN
  GEDLTRYREMSYKVTELLEEFSPVVERLGFDENFVDLTEMVEKRLQQLQSDELSAVTVSG
  HVYNNQSINLLDVLHIRLLVGSQIAAEMREAMYNQLGLTGCAGVASNKLLAKLVSGVFKP
  NQQTVLLPESCQHLIHSLNHIKEIPGIGYKTAKCLEALGINSVRDLQTFSPKILEKELGI
  SVAQRIQKLSFGEDNSPVILSGPPQSFSEEDSFKKCSSEVEAKNKIEELLASLLNRVCQD
  GRKPHTVRLIIRRYSSEKHYGRESRQCPIPSHVIQKLGTGNYDVMTPMVDILMKLFRNMV
  NVKMPFHLTLLSVCFCNLKALNTAKKGLIDYYLMPSLSTTSRSGKHSFKMKDTHMEDFPK
  DKETNRDFLPSGRIESTRTRESPLDTTNFSKEKDINEFPLCSLPEGVDQEVFKQLPVDIQ
  EEILSGKSREKFQGKGSVSCPLHASRGVLSFFSKKQMQDIPINPRDHLSSSKQVSSVSPC
  EPGTSGFNSSSSSYMSSQKDYSYYLDNRLKDERISQGPKEPQGFHFTNSNPAVSAFHSFP
  NLQSEQLFSRNHTTDSHKQTVATDSHEGLTENREPDSVDEKITFPSDIDPQVFYELPEAV
  QKELLAEWKRAGSDFHIGHK
• Function: Error-prone 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. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunoglobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.
• Tissue Specificity: Ubiquitous. Highly expressed in testis.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Termination of translesion DNA synthesis (R-HSA-5656169)
  Translesion synthesis by POLI (R-HSA-5656121)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[5]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[5]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[10]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[11]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[12]
Asthma	DISW9QNS	Limited	Genetic Variation	[13]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[11]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[14]

10 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 iota (POLI).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA polymerase iota (POLI).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA polymerase iota (POLI).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of DNA polymerase iota (POLI).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA polymerase iota (POLI).	[19]
Guanine	DMIWLJE	Phase 3	Guanine decreases the activity of DNA polymerase iota (POLI).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DNA polymerase iota (POLI).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DNA polymerase iota (POLI).	[22]
MK-886	DMT0O7H	Discontinued in Phase 2	MK-886 decreases the activity of DNA polymerase iota (POLI).	[24]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of DNA polymerase iota (POLI).	[25]

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 decreases the phosphorylation of DNA polymerase iota (POLI).	[23]

References

• [1] Overexpressed DNA polymerase iota regulated by JNK/c-Jun contributes to hypermutagenesis in bladder cancer.PLoS One. 2013 Jul 26;8(7):e69317. doi: 10.1371/journal.pone.0069317. Print 2013.
• [2] DNA polymerase iota (Pol ) promotes the migration and invasion of breast cancer cell via EGFR-ERK-mediated epithelial to mesenchymal transition.Cancer Biomark. 2019;24(3):363-370. doi: 10.3233/CBM-181516.
• [3] Altered DNA polymerase iota expression in breast cancer cells leads to a reduction in DNA replication fidelity and a higher rate of mutagenesis.Cancer Res. 2004 Aug 15;64(16):5597-607. doi: 10.1158/0008-5472.CAN-04-0603.
• [4] Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota.Nature. 2002 Oct 31;419(6910):944-7. doi: 10.1038/nature01117.
• [5] Overexpression of DNA polymerase iota (Pol) in esophageal squamous cell carcinoma.Cancer Sci. 2012 Aug;103(8):1574-9. doi: 10.1111/j.1349-7006.2012.02309.x. Epub 2012 May 30.
• [6] The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease.Int Urol Nephrol. 2019 Mar;51(3):491-502. doi: 10.1007/s11255-018-02064-3. Epub 2019 Jan 7.
• [7] Phosphorylation of ETS-1 is a critical event in DNA polymerase iota-induced invasion and metastasis of esophageal squamous cell carcinoma.Cancer Sci. 2017 Dec;108(12):2503-2510. doi: 10.1111/cas.13399. Epub 2017 Oct 8.
• [8] siRNA of DNA polymerase iota inhibits the migration and invasion in the lung cancer cell A549.Acta Biochim Biophys Sin (Shanghai). 2018 Sep 1;50(9):929-933. doi: 10.1093/abbs/gmy089.
• [9] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [10] Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes.Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3030-5. doi: 10.1158/1055-9965.EPI-09-0772. Epub 2009 Oct 27.
• [11] No association of the POLI Thr706Ala polymorphism with the risk of cervical carcinoma.Eur J Surg Oncol. 2008 Aug;34(8):916-920. doi: 10.1016/j.ejso.2007.11.008. Epub 2008 Jan 14.
• [12] Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk.Int J Cancer. 2005 May 1;114(5):730-7. doi: 10.1002/ijc.20790.
• [13] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [14] 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.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.