Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJL9ZRN)

• DOT Name: Ribonuclease H2 subunit C (RNASEH2C)
• Synonyms: RNase H2 subunit C; Aicardi-Goutieres syndrome 3 protein; AGS3; RNase H1 small subunit; Ribonuclease HI subunit C
• Gene Name: RNASEH2C
• Related Disease:
  Aicardi-Goutieres syndrome 3
  Bacteremia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Episodic kinesigenic dyskinesia 1
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gout
  Neoplasm
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Aicardi-Goutieres syndrome
  Dystonia
  Intellectual disability
• UniProt ID: RNH2C_HUMAN
• PDB ID: 3P56; 3PUF
• Pfam ID: PF08615
• Sequence:
  MESGDEAAIERHRVHLRSATLRDAVPATLHLLPCEVAVDGPAPVGRFFTPAIRQGPEGLE
  VSFRGRCLRGEEVAVPPGLVGYVMVTEEKKVSMGKPDPLRDSGTDDQEEEPLERDFDRFI
  GATANFSRFTLWGLETIPGPDAKVRGALTWPSLAAAIHAQVPED
• Function: Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging-strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: D. replication (hsa03030)
• BioCyc Pathway: MetaCyc:HS16149-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aicardi-Goutieres syndrome 3	DIS16XSH	Definitive	Autosomal recessive	[1]
Bacteremia	DIS6N9RZ	Definitive	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Posttranslational Modification	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Gout	DISHC0U7	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[11]
Prostate cancer	DISF190Y	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Aicardi-Goutieres syndrome	DIS1NH4X	Supportive	Autosomal dominant	[12]
Dystonia	DISJLFGW	Limited	Biomarker	[1]
Intellectual disability	DISMBNXP	Limited	Biomarker	[13]

9 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 Ribonuclease H2 subunit C (RNASEH2C).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ribonuclease H2 subunit C (RNASEH2C).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ribonuclease H2 subunit C (RNASEH2C).	[22]

References

• [1] Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutires syndrome and mimic congenital viral brain infection. Nat Genet. 2006 Aug;38(8):910-6. doi: 10.1038/ng1842. Epub 2006 Jul 16.
• [2] Clinical characteristics and outcomes of bacteremia due to different genomic species of Acinetobacter baumannii complex in patients with solid tumors.Infection. 2012 Feb;40(1):19-26. doi: 10.1007/s15010-011-0187-4. Epub 2011 Sep 2.
• [3] Aicardi-Goutires syndrome gene Rnaseh2c is a metastasis susceptibility gene in breast cancer.PLoS Genet. 2019 May 24;15(5):e1008020. doi: 10.1371/journal.pgen.1008020. eCollection 2019 May.
• [4] Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians.Cell Death Differ. 2019 Sep;26(9):1845-1858. doi: 10.1038/s41418-018-0255-8. Epub 2019 Jan 8.
• [5] DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression.Oncology. 2017;92(2):115-124. doi: 10.1159/000452281. Epub 2016 Dec 17.
• [6] Activator of G protein signaling 3 promotes epithelial cell proliferation in PKD.J Am Soc Nephrol. 2010 Aug;21(8):1275-80. doi: 10.1681/ASN.2009121224. Epub 2010 May 20.
• [7] Overexpression of activator of G-protein signaling 3 decreases the proliferation of esophageal squamous cell carcinoma.Pathol Res Pract. 2015 Jun;211(6):449-55. doi: 10.1016/j.prp.2014.12.016. Epub 2015 Feb 19.
• [8] Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines.Cell Oncol. 2009;31(6):475-85. doi: 10.3233/CLO-2009-0496.
• [9] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [10] Activator of G protein signaling 3 modulates prostate tumor development and progression.Carcinogenesis. 2019 Dec 31;40(12):1504-1513. doi: 10.1093/carcin/bgz076.
• [11] A role for activator of G-protein signaling 3 (AGS3) in multiple myeloma.Int J Hematol. 2014 Jan;99(1):57-68. doi: 10.1007/s12185-013-1484-8. Epub 2013 Dec 5.
• [12] Aicardi-Goutires Syndrome. 2005 Jun 29 [updated 2016 Nov 22]. 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] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] 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.