Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4K9BT7)

• DOT Name: DNA-directed RNA polymerase III subunit RPC9 (CRCP)
• Synonyms: RNA polymerase III subunit C9; Calcitonin gene-related peptide-receptor component protein; CGRP-RCP; CGRP-receptor component protein; CGRPRCP; HsC17
• Gene Name: CRCP
• Related Disease:
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Sciatic neuropathy
  Adenocarcinoma
  Stroke
• UniProt ID: RPC9_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 8ITY; 8IUE; 8IUH
• Pfam ID: PF03874
• Sequence:
  MEVKDANSALLSNYEVFQLLTDLKEQRKESGKNKHSSGQQNLNTITYETLKYISKTPCRH
  QSPEIVREFLTALKSHKLTKAEKLQLLNHRPVTAVEIQLMVEESEERLTEEQIEALLHTV
  TSILPAEPEAEQKKNTNSNVAMDEEDPA
• Function: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. With POLR3H/RPC8 forms a mobile stalk that protrudes from Pol III core and functions primarily in transcription initiation. Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as 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 ; Accessory protein for the calcitonin gene-related peptide (CGRP) receptor. It modulates CGRP responsiveness in a variety of tissues.
• Tissue Specificity: Ubiquitous. Most prevalent in testis.
• KEGG Pathway: R. polymerase (hsa03020)
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[4]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[5]
Stroke	DISX6UHX	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[10]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[14]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[15]

2 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 RPC9 (CRCP).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA-directed RNA polymerase III subunit RPC9 (CRCP).	[16]

References

• [1] Liposomal delivery of MicroRNA-7-expressing plasmid overcomes epidermal growth factor receptor tyrosine kinase inhibitor-resistance in lung cancer cells.Mol Cancer Ther. 2011 Sep;10(9):1720-7. doi: 10.1158/1535-7163.MCT-11-0220. Epub 2011 Jun 28.
• [2] Correction: RCP induces Slug expression and cancer cell invasion by stabilizing 1 integrin.Oncogene. 2019 May;38(20):3970-3971. doi: 10.1038/s41388-019-0678-9.
• [3] RCP is a human breast cancer-promoting gene with Ras-activating function.J Clin Invest. 2009 Aug;119(8):2171-83. doi: 10.1172/JCI37622. Epub 2009 Jul 20.
• [4] Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems.Neuroscience. 2003;120(3):677-94. doi: 10.1016/s0306-4522(03)00159-3.
• [5] Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line.Cancer Res. 2007 Aug 15;67(16):7807-14. doi: 10.1158/0008-5472.CAN-07-0681.
• [6] A Contemporary Meta-Analysis of Antegrade versus Retrograde Cerebral Perfusion for Thoracic Aortic Surgery.Thorac Cardiovasc Surg. 2019 Aug;67(5):351-362. doi: 10.1055/s-0038-1632389. Epub 2018 Apr 6.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [12] 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.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] 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.