Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8G3G7K)

• DOT Name: Ribonuclease H2 subunit A (RNASEH2A)
• Synonyms: RNase H2 subunit A; EC 3.1.26.4; Aicardi-Goutieres syndrome 4 protein; AGS4; RNase H(35); Ribonuclease HI large subunit; RNase HI large subunit; Ribonuclease HI subunit A
• Gene Name: RNASEH2A
• Related Disease:
  Aicardi-Goutieres syndrome 4
  Adult glioblastoma
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Chronic obstructive pulmonary disease
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Glioma
  Neoplasm
  Renal cell carcinoma
  Systemic lupus erythematosus
  Aicardi-Goutieres syndrome
  Dystonia
  Intellectual disability
• UniProt ID: RNH2A_HUMAN
• PDB ID: 3P56; 3PUF
• EC Number: 3.1.26.4
• Pfam ID: PF01351
• Sequence:
  MDLSELERDNTGRCRLSSPVPAVCRKEPCVLGVDEAGRGPVLGPMVYAICYCPLPRLADL
  EALKVADSKTLLESERERLFAKMEDTDFVGWALDVLSPNLISTSMLGRVKYNLNSLSHDT
  ATGLIQYALDQGVNVTQVFVDTVGMPETYQARLQQSFPGIEVTVKAKADALYPVVSAASI
  CAKVARDQAVKKWQFVEKLQDLDTDYGSGYPNDPKTKAWLKEHVEPVFGFPQFVRFSWRT
  AQTILEKEAEDVIWEDSASENQEGLRKITSYFLNEGSQARPRSSHRYFLERGLESATSL
• Function: Catalytic subunit of RNase HII, 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.
• KEGG Pathway: D. replication (hsa03030)
• BioCyc Pathway: MetaCyc:HS02645-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aicardi-Goutieres syndrome 4	DIS5GQQ1	Definitive	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Posttranslational Modification	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Posttranslational Modification	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[6]
Aicardi-Goutieres syndrome	DIS1NH4X	Supportive	Autosomal dominant	[7]
Dystonia	DISJLFGW	Limited	Biomarker	[8]
Intellectual disability	DISMBNXP	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ribonuclease H2 subunit A (RNASEH2A).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ribonuclease H2 subunit A (RNASEH2A).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[28]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Ribonuclease H2 subunit A (RNASEH2A).	[15]

References

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• [2] RNaseH2A is involved in human gliomagenesis through the regulation of cell proliferation and apoptosis.Oncol Rep. 2016 Jul;36(1):173-80. doi: 10.3892/or.2016.4802. Epub 2016 May 10.
• [3] Prognostic Value of RNASEH2A-, CDK1-, and CD151-Related Pathway Gene Profiling for Kidney Cancers.Int J Mol Sci. 2018 May 28;19(6):1586. doi: 10.3390/ijms19061586.
• [4] Genome-Wide Profiling of Cervical RNA-Binding Proteins Identifies Human Papillomavirus Regulation of RNASEH2A Expression by Viral E7 and E2F1.mBio. 2019 Jan 29;10(1):e02687-18. doi: 10.1128/mBio.02687-18.
• [5] A genome-wide analysis of the response to inhaled 2-agonists in chronic obstructive pulmonary disease.Pharmacogenomics J. 2016 Aug;16(4):326-35. doi: 10.1038/tpj.2015.65. Epub 2015 Oct 27.
• [6] Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus.Hum Genet. 2019 Feb;138(2):141-150. doi: 10.1007/s00439-018-01966-7. Epub 2019 Feb 1.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] 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.
• [17] 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.
• [18] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [19] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [20] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [21] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [22] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [25] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [26] 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.
• [27] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.