Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3FS9MB)

• DOT Name: DNA-directed RNA polymerase III subunit RPC2 (POLR3B)
• Synonyms: RNA polymerase III subunit C2; EC 2.7.7.6; C128; DNA-directed RNA polymerase III 127.6 kDa polypeptide; DNA-directed RNA polymerase III subunit B
• Gene Name: POLR3B
• Related Disease:
  Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism
  Cataract
  Central nervous system neoplasm
  Cerebellar ataxia
  Charcot-Marie-Tooth disease, demyelinating, IIA 1I
  Glioblastoma multiforme
  Glioma
  Intellectual disability
  Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
  Lung cancer
  Lung carcinoma
  Neoplasm
  Addison disease
  Adrenocortical insufficiency
  Trichohepatoenteric syndrome
  Obsolete endosteal sclerosis-cerebellar hypoplasia syndrome
  Obsolete hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
• UniProt ID: RPC2_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 8ITY; 8IUE; 8IUH
• EC Number: 2.7.7.6
• Pfam ID: PF04563 ; PF04561 ; PF04565 ; PF04566 ; PF04567 ; PF00562 ; PF04560
• Sequence:
  MDVLAEEFGNLTPEQLAAPIPTVEEKWRLLPAFLKVKGLVKQHIDSFNYFINVEIKKIMK
  ANEKVTSDADPMWYLKYLNIYVGLPDVEESFNVTRPVSPHECRLRDMTYSAPITVDIEYT
  RGSQRIIRNALPIGRMPIMLRSSNCVLTGKTPAEFAKLNECPLDPGGYFIVKGVEKVILI
  QEQLSKNRIIVEADRKGAVGASVTSSTHEKKSRTNMAVKQGRFYLRHNTLSEDIPIVIIF
  KAMGVESDQEIVQMIGTEEHVMAAFGPSLEECQKAQIFTQMQALKYIGNKVRRQRMWGGG
  PKKTKIEEARELLASTILTHVPVKEFNFRAKCIYTAVMVRRVILAQGDNKVDDRDYYGNK
  RLELAGQLLSLLFEDLFKKFNSEMKKIADQVIPKQRAAQFDVVKHMRQDQITNGMVNAIS
  TGNWSLKRFKMDRQGVTQVLSRLSYISALGMMTRISSQFEKTRKVSGPRSLQPSQWGMLC
  PSDTPEGEACGLVKNLALMTHITTDMEDGPIVKLASNLGVEDVNLLCGEELSYPNVFLVF
  LNGNILGVIRDHKKLVNTFRLMRRAGYINEFVSISTNLTDRCVYISSDGGRLCRPYIIVK
  KQKPAVTNKHMEELAQGYRNFEDFLHESLVEYLDVNEENDCNIALYEHTINKDTTHLEIE
  PFTLLGVCAGLIPYPHHNQSPRNTYQCAMGKQAMGTIGYNQRNRIDTLMYLLAYPQKPMV
  KTKTIELIEFEKLPAGQNATVAVMSYSGYDIEDALVLNKASLDRGFGRCLVYKNAKCTLK
  RYTNQTFDKVMGPMLDAATRKPIWRHEILDADGICSPGEKVENKQVLVNKSMPTVTQIPL
  EGSNVPQQPQYKDVPITYKGATDSYIEKVMISSNAEDAFLIKMLLRQTRRPEIGDKFSSR
  HGQKGVCGLIVPQEDMPFCDSGICPDIIMNPHGFPSRMTVGKLIELLAGKAGVLDGRFHY
  GTAFGGSKVKDVCEDLVRHGYNYLGKDYVTSGITGEPLEAYIYFGPVYYQKLKHMVLDKM
  HARARGPRAVLTRQPTEGRSRDGGLRLGEMERDCLIGYGASMLLLERLMISSDAFEVDVC
  GQCGLLGYSGWCHYCKSSCHVSSLRIPYACKLLFQELQSMNIIPRLKLSKYNE
• Function: Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. Synthesizes 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. Pol III-mediated transcription cycle proceeds through transcription initiation, transcription elongation and transcription termination stages. During transcription initiation, Pol III is recruited to DNA promoters type I, II or III with the help of general transcription factors and other specific initiation factors. Once the polymerase has escaped from the promoter it enters the elongation phase during which RNA is actively polymerized, based on complementarity with the template DNA strand. Transcription termination involves the release of the RNA transcript and polymerase from the DNA. Forms Pol III active center together with the largest subunit POLR3A/RPC1. A single-stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol III. Appends one nucleotide at a time to the 3' end of the nascent RNA, with POLR3A/RPC1 contributing a Mg(2+)-coordinating DxDGD motif, and POLR3B/RPC2 participating in the coordination of a second Mg(2+) ion and providing lysine residues believed to facilitate Watson-Crick base pairing between the incoming nucleotide and template base. Typically, Mg(2+) ions direct a 5' nucleoside triphosphate to form a phosphodiester bond with the 3' hydroxyl of the preceding nucleotide of the nascent RNA, with the elimination of pyrophosphate. Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as a nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway.
• KEGG Pathway:
  R. polymerase (hsa03020)
  Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  RNA Polymerase III Chain Elongation (R-HSA-73780)
  RNA Polymerase III Transcription Termination (R-HSA-73980)
  RNA Polymerase III Abortive And Retractive Initiation (R-HSA-749476)
  RNA Polymerase III Transcription Initiation From Type 1 Promoter (R-HSA-76061)
  RNA Polymerase III Transcription Initiation From Type 2 Promoter (R-HSA-76066)
  RNA Polymerase III Transcription Initiation From Type 3 Promoter (R-HSA-76071)
  Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	DISLAPXW	Definitive	Autosomal recessive	[1]
Cataract	DISUD7SL	Strong	Genetic Variation	[2]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[4]
Charcot-Marie-Tooth disease, demyelinating, IIA 1I	DISS7ZM9	Strong	Autosomal dominant	[5]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[3]
Glioma	DIS5RPEH	Strong	Genetic Variation	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	DISM7VEP	Strong	Genetic Variation	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Addison disease	DIS7HNOH	moderate	Genetic Variation	[10]
Adrenocortical insufficiency	DISZ0CPT	moderate	Genetic Variation	[10]
Trichohepatoenteric syndrome	DISL3ODF	moderate	Biomarker	[10]
Obsolete endosteal sclerosis-cerebellar hypoplasia syndrome	DISAWEN9	Supportive	Autosomal recessive	[11]
Obsolete hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome	DISUVCMS	Supportive	Autosomal recessive	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[25]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DNA-directed RNA polymerase III subunit RPC2 (POLR3B).	[19]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts.Clin Neuroradiol. 2017 Jun;27(2):213-220. doi: 10.1007/s00062-015-0472-1. Epub 2015 Oct 19.
• [3] Genome-wide association study identifies multiple susceptibility loci for glioma.Nat Commun. 2015 Oct 1;6:8559. doi: 10.1038/ncomms9559.
• [4] A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene.Clin Genet. 2019 Mar;95(3):415-419. doi: 10.1111/cge.13489. Epub 2019 Jan 8.
• [5] De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy. Am J Hum Genet. 2021 Jan 7;108(1):186-193. doi: 10.1016/j.ajhg.2020.12.002.
• [6] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [7] A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report.BMC Pediatr. 2018 Apr 4;18(1):126. doi: 10.1186/s12887-018-1108-9.
• [8] Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q.Cancer Epidemiol Biomarkers Prev. 2020 Feb;29(2):434-442. doi: 10.1158/1055-9965.EPI-19-0887. Epub 2019 Dec 11.
• [9] INMAP overexpression inhibits cell proliferation, induces genomic instability and functions through p53/p21 pathways.PLoS One. 2015 Jan 30;10(1):e0115704. doi: 10.1371/journal.pone.0115704. eCollection 2015.
• [10] Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.BMC Med Genet. 2015 Jul 25;16:53. doi: 10.1186/s12881-015-0203-0.
• [11] Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder. Eur J Hum Genet. 2017 Aug;25(8):1011-1014. doi: 10.1038/ejhg.2017.73. Epub 2017 Jun 7.
• [12] POLR3-Related Leukodystrophy. 2012 Aug 2 [updated 2017 May 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] 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.
• [21] 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.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] 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.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.