Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1WXFVY)

• DOT Name: DNA polymerase alpha catalytic subunit (POLA1)
• Synonyms: EC 2.7.7.7; DNA polymerase alpha catalytic subunit p180
• Gene Name: POLA1
• Related Disease:
  X-linked intellectual disability, van Esch type
  X-linked reticulate pigmentary disorder
• UniProt ID: DPOLA_HUMAN
• PDB ID: 1K0P; 1K18; 1N5G; 4Q5V; 4QCL; 4Y97; 5EXR; 5IUD; 6AS7; 7N2M; 7OPL; 7U5C; 8B9D; 8D0B; 8D0K; 8D96; 8D9D
• EC Number: 2.7.7.7
• Pfam ID: PF12254 ; PF00136 ; PF03104 ; PF08996
• Sequence:
  MAPVHGDDSLSDSGSFVSSRARREKKSKKGRQEALERLKKAKAGEKYKYEVEDFTGVYEE
  VDEEQYSKLVQARQDDDWIVDDDGIGYVEDGREIFDDDLEDDALDADEKGKDGKARNKDK
  RNVKKLAVTKPNNIKSMFIACAGKKTADKAVDLSKDGLLGDILQDLNTETPQITPPPVMI
  LKKKRSIGASPNPFSVHTATAVPSGKIASPVSRKEPPLTPVPLKRAEFAGDDVQVESTEE
  EQESGAMEFEDGDFDEPMEVEEVDLEPMAAKAWDKESEPAEEVKQEADSGKGTVSYLGSF
  LPDVSCWDIDQEGDSSFSVQEVQVDSSHLPLVKGADEEQVFHFYWLDAYEDQYNQPGVVF
  LFGKVWIESAETHVSCCVMVKNIERTLYFLPREMKIDLNTGKETGTPISMKDVYEEFDEK
  IATKYKIMKFKSKPVEKNYAFEIPDVPEKSEYLEVKYSAEMPQLPQDLKGETFSHVFGTN
  TSSLELFLMNRKIKGPCWLEVKSPQLLNQPVSWCKVEAMALKPDLVNVIKDVSPPPLVVM
  AFSMKTMQNAKNHQNEIIAMAALVHHSFALDKAAPKPPFQSHFCVVSKPKDCIFPYAFKE
  VIEKKNVKVEVAATERTLLGFFLAKVHKIDPDIIVGHNIYGFELEVLLQRINVCKAPHWS
  KIGRLKRSNMPKLGGRSGFGERNATCGRMICDVEISAKELIRCKSYHLSELVQQILKTER
  VVIPMENIQNMYSESSQLLYLLEHTWKDAKFILQIMCELNVLPLALQITNIAGNIMSRTL
  MGGRSERNEFLLLHAFYENNYIVPDKQIFRKPQQKLGDEDEEIDGDTNKYKKGRKKAAYA
  GGLVLDPKVGFYDKFILLLDFNSLYPSIIQEFNICFTTVQRVASEAQKVTEDGEQEQIPE
  LPDPSLEMGILPREIRKLVERRKQVKQLMKQQDLNPDLILQYDIRQKALKLTANSMYGCL
  GFSYSRFYAKPLAALVTYKGREILMHTKEMVQKMNLEVIYGDTDSIMINTNSTNLEEVFK
  LGNKVKSEVNKLYKLLEIDIDGVFKSLLLLKKKKYAALVVEPTSDGNYVTKQELKGLDIV
  RRDWCDLAKDTGNFVIGQILSDQSRDTIVENIQKRLIEIGENVLNGSVPVSQFEINKALT
  KDPQDYPDKKSLPHVHVALWINSQGGRKVKAGDTVSYVICQDGSNLTASQRAYAPEQLQK
  QDNLTIDTQYYLAQQIHPVVARICEPIDGIDAVLIATWLGLDPTQFRVHHYHKDEENDAL
  LGGPAQLTDEEKYRDCERFKCPCPTCGTENIYDNVFDGSGTDMEPSLYRCSNIDCKASPL
  TFTVQLSNKLIMDIRRFIKKYYDGWLICEEPTCRNRTRHLPLQFSRTGPLCPACMKATLQ
  PEYSDKSLYTQLCFYRYIFDAECALEKLTTDHEKDKLKKQFFTPKVLQDYRKLKNTAEQF
  LSRSGYSEVNLSKLFAGCAVKS
• Function: Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, a regulatory subunit POLA2 and two primase subunits PRIM1 and PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses.
• KEGG Pathway: D. replication (hsa03030)
• Reactome Pathway:
  Polymerase switching on the C-strand of the telomere (R-HSA-174411)
  Telomere C-strand synthesis initiation (R-HSA-174430)
  DNA replication initiation (R-HSA-68952)
  Activation of the pre-replicative complex (R-HSA-68962)
  Polymerase switching (R-HSA-69091)
  Removal of the Flap Intermediate (R-HSA-69166)
  Processive synthesis on the lagging strand (R-HSA-69183)
  G1/S-Specific Transcription (R-HSA-69205)
  Defective pyroptosis (R-HSA-9710421)
  Inhibition of replication initiation of damaged DNA by RB1/E2F1 (R-HSA-113501)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked intellectual disability, van Esch type	DISO3N3T	Definitive	X-linked recessive	[1]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	X-linked	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	DNA polymerase alpha catalytic subunit (POLA1) increases the response to substance of Irinotecan.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA polymerase alpha catalytic subunit (POLA1).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of DNA polymerase alpha catalytic subunit (POLA1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of DNA polymerase alpha catalytic subunit (POLA1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA polymerase alpha catalytic subunit (POLA1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase alpha catalytic subunit (POLA1).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[18]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[19]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[20]
Aphidicolin	DM71C6D	Discontinued in Phase 1	Aphidicolin decreases the activity of DNA polymerase alpha catalytic subunit (POLA1).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[6]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of DNA polymerase alpha catalytic subunit (POLA1).	[24]

References

• [1] Defective DNA Polymerase -Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism. Am J Hum Genet. 2019 May 2;104(5):957-967. doi: 10.1016/j.ajhg.2019.03.006. Epub 2019 Apr 18.
• [2] DNA polymerase- regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat Immunol. 2016 May;17(5):495-504. doi: 10.1038/ni.3409. Epub 2016 Mar 28.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [11] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [14] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [19] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [20] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] Effect of aphidicolin on viral and human DNA polymerases. Biochem Biophys Res Commun. 1979 Jun 27;88(4):1194-202. doi: 10.1016/0006-291x(79)91106-9.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [25] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.