Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5MSK10)

• DOT Name: DNA-directed RNA polymerase III subunit RPC1 (POLR3A)
• Synonyms: RNA polymerase III subunit C1; EC 2.7.7.6; DNA-directed RNA polymerase III largest subunit; DNA-directed RNA polymerase III subunit A; RNA polymerase III 155 kDa subunit; RPC155; RNA polymerase III subunit C160
• Gene Name: POLR3A
• Related Disease:
  Odontoleukodystrophy
  Advanced cancer
  Attention deficit hyperactivity disorder
  Autoimmune disease
  Cerebellar ataxia
  Cockayne syndrome
  Hereditary spastic paraplegia
  Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
  Long QT syndrome 1
  Neoplasm
  Spastic ataxia
  Trichohepatoenteric syndrome
  Wiedemann-Rautenstrauch syndrome
  Connective tissue disorder
  Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome
  Obsolete hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
  Tremor-ataxia-central hypomyelination syndrome
  Acute myelogenous leukaemia
  Scleroderma
  Systemic sclerosis
• UniProt ID: RPC1_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: PF04997 ; PF00623 ; PF04983 ; PF05000 ; PF04998
• Sequence:
  MVKEQFRETDVAKKISHICFGMKSPEEMRQQAHIQVVSKNLYSQDNQHAPLLYGVLDHRM
  GTSEKDRPCETCGKNLADCLGHYGYIDLELPCFHVGYFRAVIGILQMICKTCCHIMLSQE
  EKKQFLDYLKRPGLTYLQKRGLKKKISDKCRKKNICHHCGAFNGTVKKCGLLKIIHEKYK
  TNKKVVDPIVSNFLQSFETAIEHNKEVEPLLGRAQENLNPLVVLNLFKRIPAEDVPLLLM
  NPEAGKPSDLILTRLLVPPLCIRPSVVSDLKSGTNEDDLTMKLTEIIFLNDVIKKHRISG
  AKTQMIMEDWDFLQLQCALYINSELSGIPLNMAPKKWTRGFVQRLKGKQGRFRGNLSGKR
  VDFSGRTVISPDPNLRIDEVAVPVHVAKILTFPEKVNKANINFLRKLVQNGPEVHPGANF
  IQQRHTQMKRFLKYGNREKMAQELKYGDIVERHLIDGDVVLFNRQPSLHKLSIMAHLARV
  KPHRTFRFNECVCTPYNADFDGDEMNLHLPQTEEAKAEALVLMGTKANLVTPRNGEPLIA
  AIQDFLTGAYLLTLKDTFFDRAKACQIIASILVGKDEKIKVRLPPPTILKPVTLWTGKQI
  FSVILRPSDDNPVRANLRTKGKQYCGKGEDLCANDSYVTIQNSELMSGSMDKGTLGSGSK
  NNIFYILLRDWGQNEAADAMSRLARLAPVYLSNRGFSIGIGDVTPGQGLLKAKYELLNAG
  YKKCDEYIEALNTGKLQQQPGCTAEETLEALILKELSVIRDHAGSACLRELDKSNSPLTM
  ALCGSKGSFINISQMIACVGQQAISGSRVPDGFENRSLPHFEKHSKLPAAKGFVANSFYS
  GLTPTEFFFHTMAGREGLVDTAVKTAETGYMQRRLVKSLEDLCSQYDLTVRSSTGDIIQF
  IYGGDGLDPAAMEGKDEPLEFKRVLDNIKAVFPCPSEPALSKNELILTTESIMKKSEFLC
  CQDSFLQEIKKFIKGVSEKIKKTRDKYGINDNGTTEPRVLYQLDRITPTQVEKFLETCRD
  KYMRAQMEPGSAVGALCAQSIGEPGTQMTLKTFHFAGVASMNITLGVPRIKEIINASKAI
  STPIITAQLDKDDDADYARLVKGRIEKTLLGEISEYIEEVFLPDDCFILVKLSLERIRLL
  RLEVNAETVRYSICTSKLRVKPGDVAVHGEAVVCVTPRENSKSSMYYVLQFLKEDLPKVV
  VQGIPEVSRAVIHIDEQSGKEKYKLLVEGDNLRAVMATHGVKGTRTTSNNTYEVEKTLGI
  EAARTTIINEIQYTMVNHGMSIDRRHVMLLSDLMTYKGEVLGITRFGLAKMKESVLMLAS
  FEKTADHLFDAAYFGQKDSVCGVSECIIMGIPMNIGTGLFKLLHKADRDPNPPKRPLIFD
  TNEFHIPLVT
• 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 second largest subunit POLR3B/RPC2. 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.
• Tissue Specificity: Expressed in the brain, in the cortex and the white matter (at protein level).
• 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

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Odontoleukodystrophy	DISL7LA1	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Cockayne syndrome	DISW6GL2	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[4]
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	DISM7VEP	Strong	Autosomal recessive	[6]
Long QT syndrome 1	DISXK5OU	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Spastic ataxia	DISIRRA9	Strong	Genetic Variation	[9]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[10]
Wiedemann-Rautenstrauch syndrome	DIS11Z1N	Strong	Autosomal recessive	[11]
Connective tissue disorder	DISKXBS3	moderate	Biomarker	[12]
Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome	DISZPUWK	Supportive	Autosomal recessive	[13]
Obsolete hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome	DISUVCMS	Supportive	Autosomal recessive	[6]
Tremor-ataxia-central hypomyelination syndrome	DIS6ASFI	Supportive	Autosomal recessive	[14]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[15]
Scleroderma	DISVQ342	Limited	Biomarker	[2]
Systemic sclerosis	DISF44L6	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase III subunit RPC1 (POLR3A).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA-directed RNA polymerase III subunit RPC1 (POLR3A).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA-directed RNA polymerase III subunit RPC1 (POLR3A).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-directed RNA polymerase III subunit RPC1 (POLR3A).	[20]

2 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 III subunit RPC1 (POLR3A).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA-directed RNA polymerase III subunit RPC1 (POLR3A).	[19]

References

• [1] Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis. Brain. 2019 Apr 1;142(4):e12. doi: 10.1093/brain/awz041.
• [2] Protective Effect Against Cancer of Antibodies to the LargeSubunits of Both RNA Polymerases I and III in Scleroderma.Arthritis Rheumatol. 2019 Sep;71(9):1571-1579. doi: 10.1002/art.40893. Epub 2019 Aug 1.
• [3] A Systematic Review of the Use of Bupropion for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.J Child Adolesc Psychopharmacol. 2017 Mar;27(2):112-116. doi: 10.1089/cap.2016.0124. Epub 2016 Nov 4.
• [4] Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.Brain. 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095.
• [5] Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.Hum Genet. 2018 Dec;137(11-12):921-939. doi: 10.1007/s00439-018-1957-1. Epub 2018 Nov 19.
• [6] Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014.
• [7] Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome.Am J Hum Genet. 2018 Dec 6;103(6):968-975. doi: 10.1016/j.ajhg.2018.10.010. Epub 2018 Nov 7.
• [8] Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III.Cancer Res. 2017 Sep 15;77(18):4934-4946. doi: 10.1158/0008-5472.CAN-16-3541. Epub 2017 Jul 20.
• [9] POLR3A-related spastic ataxia: new mutations and a look into the phenotype.J Neurol. 2020 Feb;267(2):324-330. doi: 10.1007/s00415-019-09574-9. Epub 2019 Oct 21.
• [10] Wiedemann-Rautenstrauch syndrome: A phenotype analysis.Am J Med Genet A. 2017 Jul;173(7):1763-1772. doi: 10.1002/ajmg.a.38246. Epub 2017 Apr 26.
• [11] Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. Am J Med Genet A. 2016 Dec;170(12):3343-3346. doi: 10.1002/ajmg.a.37960. Epub 2016 Sep 9.
• [12] Association of the autoimmune disease scleroderma with an immunologic response to cancer.Science. 2014 Jan 10;343(6167):152-7. doi: 10.1126/science.1246886. Epub 2013 Dec 5.
• [13] Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet. 2011 Nov 11;89(5):644-51. doi: 10.1016/j.ajhg.2011.10.003. Epub 2011 Oct 27.
• [14] Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31. Neurogenetics. 2010 Oct;11(4):457-64. doi: 10.1007/s10048-010-0251-8. Epub 2010 Jul 17.
• [15] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [16] 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.
• [17] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [18] 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.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.