Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT7L25X)

• DOT Name: Ribonuclease H1 (RNASEH1)
• Synonyms: RNase H1; EC 3.1.26.4; Ribonuclease H type II
• Gene Name: RNASEH1
• Related Disease:
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Mitochondrial encephalomyopathy
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
  Schmid metaphyseal chondrodysplasia
  Tuberculosis
  Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
  Type-1 diabetes
  Leigh syndrome
  Mitochondrial disease
• UniProt ID: RNH1_HUMAN
• PDB ID: 2QK9; 2QKB; 2QKK; 3BSU; 6VRD
• EC Number: 3.1.26.4
• Pfam ID: PF01693 ; PF00075
• Sequence:
  MSWLLFLAHRVALAALPCRRGSRGFGMFYAVRRGRKTGVFLTWNECRAQVDRFPAARFKK
  FATEDEAWAFVRKSASPEVSEGHENQHGQESEAKASKRLREPLDGDGHESAEPYAKHMKP
  SVEPAPPVSRDTFSYMGDFVVVYTDGCCSSNGRRRPRAGIGVYWGPGHPLNVGIRLPGRQ
  TNQRAEIHAACKAIEQAKTQNINKLVLYTDSMFTINGITNWVQGWKKNGWKTSAGKEVIN
  KEDFVALERLTQGMDIQWMHVPGHSGFIGNEEADRLAREGAKQSED
• Function: Endonuclease that specifically degrades the RNA of RNA-DNA hybrids. Plays a role in RNA polymerase II (RNAp II) transcription termination by degrading R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site and behind the elongating RNAp II.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: D. replication (hsa03030)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[3]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[4]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2	DIS1DL5R	Strong	Autosomal recessive	[5]
Schmid metaphyseal chondrodysplasia	DISX2EGR	Strong	Genetic Variation	[6]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[7]
Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy	DISUXRUM	Supportive	Autosomal dominant	[4]
Type-1 diabetes	DIS7HLUB	Disputed	Genetic Variation	[8]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[9]
Mitochondrial disease	DISKAHA3	Limited	Genetic Variation	[10]

13 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 Ribonuclease H1 (RNASEH1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribonuclease H1 (RNASEH1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ribonuclease H1 (RNASEH1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ribonuclease H1 (RNASEH1).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Ribonuclease H1 (RNASEH1).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Ribonuclease H1 (RNASEH1).	[16]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Ribonuclease H1 (RNASEH1).	[17]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Ribonuclease H1 (RNASEH1).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ribonuclease H1 (RNASEH1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ribonuclease H1 (RNASEH1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ribonuclease H1 (RNASEH1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ribonuclease H1 (RNASEH1).	[13]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Ribonuclease H1 (RNASEH1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ribonuclease H1 (RNASEH1).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ribonuclease H1 (RNASEH1).	[20]

References

• [1] Genome-derived cytosolic DNA contributes to type I interferon expression and immunogenicity of B-cell lymphoma cells.Cytokine. 2015 Dec;76(2):581-582. doi: 10.1016/j.cyto.2015.05.024. Epub 2015 Jun 9.
• [2] Differentially expressed mitochondrial genes in breast cancer cells: Potential new targets for anti-cancer therapies.Gene. 2017 Jan 5;596:45-52. doi: 10.1016/j.gene.2016.10.005. Epub 2016 Oct 6.
• [3] A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.Cell. 2017 Jun 1;169(6):1105-1118.e15. doi: 10.1016/j.cell.2017.05.010.
• [4] RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy. Am J Hum Genet. 2015 Jul 2;97(1):186-93. doi: 10.1016/j.ajhg.2015.05.013. Epub 2015 Jun 18.
• [5] Failure to produce mitochondrial DNA results in embryonic lethality in Rnaseh1 null mice. Mol Cell. 2003 Mar;11(3):807-15. doi: 10.1016/s1097-2765(03)00088-1.
• [6] Genetic changes in the RNA components of RNase MRP and RNase P in Schmid metaphyseal chondrodysplasia.J Med Genet. 2003 Oct;40(10):741-6. doi: 10.1136/jmg.40.10.741.
• [7] Division of labor among Mycobacterium smegmatis RNase H enzymes: RNase H1 activity of RnhA or RnhC is essential for growth whereas RnhB and RnhA guard against killing by hydrogen peroxide in stationary phase.Nucleic Acids Res. 2017 Jan 9;45(1):1-14. doi: 10.1093/nar/gkw1046. Epub 2016 Nov 28.
• [8] RNASEH1 gene variants are associated with autoimmune type 1 diabetes in Colombia.J Endocrinol Invest. 2018 Jul;41(7):755-764. doi: 10.1007/s40618-017-0797-5. Epub 2017 Dec 4.
• [9] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [10] The Jekyll and Hyde character of RNase H1 and its multiple roles in mitochondrial DNA metabolism.DNA Repair (Amst). 2019 Dec;84:102630. doi: 10.1016/j.dnarep.2019.06.001. Epub 2019 Jun 4.
• [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] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [19] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.