Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP6UQUP)

• DOT Name: 2-5A-dependent ribonuclease (RNASEL)
• Synonyms: 2-5A-dependent RNase; EC 3.1.26.-; Ribonuclease 4; Ribonuclease L; RNase L
• Gene Name: RNASEL
• Related Disease: Prostate cancer, hereditary, 1
• UniProt ID: RN5A_HUMAN
• PDB ID: 1WDY; 4G8K; 4G8L; 4OAU; 4OAV
• EC Number: 3.1.26.-
• Pfam ID: PF12796 ; PF13857 ; PF00069 ; PF06479
• Sequence:
  MESRDHNNPQEGPTSSSGRRAAVEDNHLLIKAVQNEDVDLVQQLLEGGANVNFQEEEGGW
  TPLHNAVQMSREDIVELLLRHGADPVLRKKNGATPFILAAIAGSVKLLKLFLSKGADVNE
  CDFYGFTAFMEAAVYGKVKALKFLYKRGANVNLRRKTKEDQERLRKGGATALMDAAEKGH
  VEVLKILLDEMGADVNACDNMGRNALIHALLSSDDSDVEAITHLLLDHGADVNVRGERGK
  TPLILAVEKKHLGLVQRLLEQEHIEINDTDSDGKTALLLAVELKLKKIAELLCKRGASTD
  CGDLVMTARRNYDHSLVKVLLSHGAKEDFHPPAEDWKPQSSHWGAALKDLHRIYRPMIGK
  LKFFIDEKYKIADTSEGGIYLGFYEKQEVAVKTFCEGSPRAQREVSCLQSSRENSHLVTF
  YGSESHRGHLFVCVTLCEQTLEACLDVHRGEDVENEEDEFARNVLSSIFKAVQELHLSCG
  YTHQDLQPQNILIDSKKAAHLADFDKSIKWAGDPQEVKRDLEDLGRLVLYVVKKGSISFE
  DLKAQSNEEVVQLSPDEETKDLIHRLFHPGEHVRDCLSDLLGHPFFWTWESRYRTLRNVG
  NESDIKTRKSESEILRLLQPGPSEHSKSFDKWTTKINECVMKKMNKFYEKRGNFYQNTVG
  DLLKFIRNLGEHIDEEKHKKMKLKIGDPSLYFQKTFPDLVIYVYTKLQNTEYRKHFPQTH
  SPNKPQCDGAGGASGLASPGC
• Function: Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis. Might play a central role in the regulation of mRNA turnover. Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length.
• Tissue Specificity: Highly expressed in spleen and thymus followed by prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Hepatitis C (hsa05160)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  Interferon alpha/beta signaling (R-HSA-909733)
  OAS antiviral response (R-HSA-8983711)
• BioCyc Pathway: MetaCyc:HS06069-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer, hereditary, 1	DISE2P4L	Limited	Autosomal dominant	[1]

10 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 2-5A-dependent ribonuclease (RNASEL).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 2-5A-dependent ribonuclease (RNASEL).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of 2-5A-dependent ribonuclease (RNASEL).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[2]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of 2-5A-dependent ribonuclease (RNASEL).	[11]

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 2-5A-dependent ribonuclease (RNASEL).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 2-5A-dependent ribonuclease (RNASEL).	[9]

References

• [1] 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.
• [2] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [3] 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.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [11] Defects in TLR3 expression and RNase L activation lead to decreased MnSOD expression and insulin resistance in muscle cells of obese people. Cell Death Dis. 2014 Mar 20;5(3):e1136. doi: 10.1038/cddis.2014.104.