Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEGR9C2)

• DOT Name: DNA-directed RNA polymerase I subunit RPA34 (POLR1G)
• Synonyms: A34.5; Antisense to ERCC-1 protein; ASE-1; CD3-epsilon-associated protein; CD3E-associated protein; DNA-directed RNA polymerase I subunit G; RNA polymerase I-associated factor PAF49
• Gene Name: POLR1G
• UniProt ID: RPA34_HUMAN
• PDB ID: 7OB9; 7OBA; 7OBB; 7VBA; 7VBB; 7VBC; 8A43
• Pfam ID: PF08208
• Sequence:
  MEEPQAGDAARFSCPPNFTAKPPASESPRFSLEALTGPDTELWLIQAPADFAPECFNGRH
  VPLSGSQIVKGKLAGKRHRYRVLSSCPQAGEATLLAPSTEAGGGLTCASAPQGTLRILEG
  PQQSLSGSPLQPIPASPPPQIPPGLRPRFCAFGGNPPVTGPRSALAPNLLTSGKKKKEMQ
  VTEAPVTQEAVNGHGALEVDMALGSPEMDVRKKKKKKNQQLKEPEAAGPVGTEPTVETLE
  PLGVLFPSTTKKRKKPKGKETFEPEDKTVKQEQINTEPLEDTVLSPTKKRKRQKGTEGME
  PEEGVTVESQPQVKVEPLEEAIPLPPTKKRKKEKGQMAMMEPGTEAMEPVEPEMKPLESP
  GGTMAPQQPEGAKPQAQAALAAPKKKTKKEKQQDATVEPETEVVGPELPDDLEPQAAPTS
  TKKKKKKKERGHTVTEPIQPLEPELPGEGQPEARATPGSTKKRKKQSQESRMPETVPQEE
  MPGPPLNSESGEEAPTGRDKKRKQQQQQPV
• Function: Component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates. Involved in UBTF-activated transcription, presumably at a step following PIC formation; [Isoform 2]: Has been described as a component of preformed T-cell receptor (TCR) complex.
• 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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[12]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of DNA-directed RNA polymerase I subunit RPA34 (POLR1G).	[3]

References

• [1] 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.
• [2] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [3] 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.
• [4] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [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] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.