Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT30S3SB)

• DOT Name: DNA-directed RNA polymerase I subunit RPA12 (POLR1H)
• Synonyms: DNA-directed RNA polymerase I subunit H; Zinc ribbon domain-containing protein 1
• Gene Name: POLR1H
• UniProt ID: RPA12_HUMAN
• PDB ID: 7OB9; 7OBA; 7OBB; 7VBA; 7VBB; 7VBC; 8A43
• Pfam ID: PF01096
• Sequence:
  MSVMDLANTCSSFQSDLDFCSDCGSVLPLPGAQDTVTCIRCGFNINVRDFEGKVVKTSVV
  FHQLGTAMPMSVEEGPECQGPVVDRRCPRCGHEGMAYHTRQMRSADEGQTVFYTCTNCKF
  QEKEDS
• Function: Core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates. Can mediate Pol I proofreading of the nascent RNA transcript. Anchors into the Pol I active site to monitor transcription fidelity and cleave mis-incorporated 5'-ribonucleotides.
• KEGG Pathway: R. polymerase (hsa03020)
• Reactome Pathway:
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  RNA Polymerase I Transcription Termination (R-HSA-73863)
  NoRC negatively regulates rRNA expression (R-HSA-427413)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	DNA-directed RNA polymerase I subunit RPA12 (POLR1H) decreases the response to substance of Methotrexate.	[17]
Etoposide	DMNH3PG	Approved	DNA-directed RNA polymerase I subunit RPA12 (POLR1H) decreases the response to substance of Etoposide.	[18]

15 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-directed RNA polymerase I subunit RPA12 (POLR1H).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[9]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA-directed RNA polymerase I subunit RPA12 (POLR1H).	[11]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [11] 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.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] 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.
• [14] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] ZNRD1 mediates resistance of gastric cancer cells to methotrexate by regulation of IMPDH2 and Bcl-2. Biochem Cell Biol. 2006 Apr;84(2):199-206. doi: 10.1139/o05-173.
• [18] Overexpression of ZNRD1 promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. Cancer Biol Ther. 2004 Apr;3(4):377-81. doi: 10.4161/cbt.3.4.724. Epub 2004 Apr 17.