Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7DVQB0)

• DOT Name: DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C)
• Synonyms: DNA-directed RNA polymerase I subunit C; RNA polymerases I and III subunit AC1; AC40; DNA-directed RNA polymerases I and III 40 kDa polypeptide; RPA40; RPA39; RPC40
• Gene Name: POLR1C
• Related Disease:
  Allergic rhinitis
  Dystonia
  Hypomyelinating leukodystrophy 11
  Leukodystrophy
  Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
  Treacher Collins syndrome 3
  Obsolete hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
  Treacher-Collins syndrome
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: RPAC1_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 7OB9; 7OBA; 7OBB; 7VBA; 7VBB; 7VBC; 8A43; 8ITY; 8IUE; 8IUH
• Pfam ID: PF01000 ; PF01193
• Sequence:
  MAASQAVEEMRSRVVLGEFGVRNVHTTDFPGNYSGYDDAWDQDRFEKNFRVDVVHMDENS
  LEFDMVGIDAAIANAFRRILLAEVPTMAVEKVLVYNNTSIVQDEILAHRLGLIPIHADPR
  LFEYRNQGDEEGTEIDTLQFRLQVRCTRNPHAAKDSSDPNELYVNHKVYTRHMTWIPLGN
  QADLFPEGTIRPVHDDILIAQLRPGQEIDLLMHCVKGIGKDHAKFSPVATASYRLLPDIT
  LLEPVEGEAAEELSRCFSPGVIEVQEVQGKKVARVANPRLDTFSREIFRNEKLKKVVRLA
  RVRDHYIFSVESTGVLPPDVLVSEAIKVLMGKCRRFLDELDAVQMD
• Function: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I and III which synthesize ribosomal RNA precursors and short non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs, respectively. POLR1C/RPAC1 is part of the polymerase core and may function as a clamp element that moves to open and close the cleft.
• KEGG Pathway:
  R. polymerase (hsa03020)
  Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  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 III Chain Elongation (R-HSA-73780)
  RNA Polymerase I Transcription Termination (R-HSA-73863)
  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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[1]
Dystonia	DISJLFGW	Strong	Genetic Variation	[2]
Hypomyelinating leukodystrophy 11	DISODKL0	Strong	Autosomal recessive	[3]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[2]
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	DISM7VEP	Strong	GermlineCausalMutation	[4]
Treacher Collins syndrome 3	DISOCTA4	Strong	Autosomal recessive	[5]
Obsolete hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome	DISUVCMS	Supportive	Autosomal recessive	[4]
Treacher-Collins syndrome	DIS2GXZ1	Supportive	Autosomal dominant	[6]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[7]

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 polymerases I and III subunit RPAC1 (POLR1C).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA-directed RNA polymerases I and III subunit RPAC1 (POLR1C).	[20]

References

• [1] Comparison of Long-term Efficacy of Subcutaneous Immunotherapy in Pediatric and Adult Patients With Allergic Rhinitis.Allergy Asthma Immunol Res. 2019 Jan;11(1):68-78. doi: 10.4168/aair.2019.11.1.68.
• [2] Novel POLR1C mutation in RNA polymerase III-related leukodystrophy with severe myoclonus and dystonia.Mol Genet Genomic Med. 2019 Sep;7(9):e914. doi: 10.1002/mgg3.914. Epub 2019 Jul 31.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623.
• [5] [Anthroposophic medicine]. Tidsskr Nor Laegeforen. 1986 Feb 20;106(5):426-31.
• [6] Treacher Collins Syndrome. 2004 Jul 20 [updated 2020 Aug 20]. 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.
• [7] Hypofractionated radiation therapy versus chemotherapy with temozolomide in patients affected by RPA class V and VI glioblastoma: a randomized phase II trial.J Neurooncol. 2019 Jul;143(3):447-455. doi: 10.1007/s11060-019-03175-2. Epub 2019 May 4.
• [8] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [9] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.