Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW8KZAU)

• DOT Name: Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16)
• Synonyms: EC 3.6.4.13; ATP-dependent RNA helicase #3; DEAH-box protein 16
• Gene Name: DHX16
• Related Disease:
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  Advanced cancer
  Amyotrophic lateral sclerosis type 4
  Blindness
  Chronic renal failure
  Connective tissue disorder
  Creutzfeldt Jacob disease
  End-stage renal disease
  Hepatitis C virus infection
  Juvenile amyotrophic lateral sclerosis
  Multiple sclerosis
  Neuromuscular disease and ocular or auditory anomalies with or without seizures
  Retinitis pigmentosa
  Rheumatoid arthritis
  Systemic lupus erythematosus
  Werner syndrome
  Dilated cardiomyopathy
  Systemic sclerosis
  Malaria
• UniProt ID: DHX16_HUMAN
• PDB ID: 5Z56; 5Z57; 5Z58; 6FF7; 7DVQ; 7QTT; 8CH6
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF21010 ; PF04408 ; PF00271 ; PF07717
• Sequence:
  MATPAGLERWVQDELHSVLGLSERHVAQFLIGTAQRCTSAEEFVQRLRDTDTLDLSGPAR
  DFALRLWNKVPRKAVVEKPARAAEREARALLEKNRSYRLLEDSEESSEETVSRAGSSLQK
  KRKKRKHLRKKREEEEEEEASEKGKKKTGGSKQQTEKPESEDEWERTERERLQDLEERDA
  FAERVRQRDKDRTRNVLERSDKKAYEEAQKRLKMAEEDRKAMVPELRKKSRREYLAKRER
  EKLEDLEAELADEEFLFGDVELSRHERQELKYKRRVRDLAREYRAAGEQEKLEATNRYHM
  PKETRGQPARAVDLVEEESGAPGEEQRRWEEARLGAASLKFGARDAASQEPKYQLVLEEE
  ETIEFVRATQLQGDEEPSAPPTSTQAQQKESIQAVRRSLPVFPFREELLAAIANHQVLII
  EGETGSGKTTQIPQYLFEEGYTNKGMKIACTQPRRVAAMSVAARVAREMGVKLGNEVGYS
  IRFEDCTSERTVLRYMTDGMLLREFLSEPDLASYSVVMVDEAHERTLHTDILFGLIKDVA
  RFRPELKVLVASATMDTARFSTFFDDAPVFRIPGRRFPVDIFYTKAPEADYLEACVVSVL
  QIHVTQPPGDILVFLTGQEEIEAACEMLQDRCRRLGSKIRELLVLPIYANLPSDMQARIF
  QPTPPGARKVVVATNIAETSLTIEGIIYVLDPGFCKQKSYNPRTGMESLTVTPCSKASAN
  QRAGRAGRVAAGKCFRLYTAWAYQHELEETTVPEIQRTSLGNVVLLLKSLGIHDLMHFDF
  LDPPPYETLLLALEQLYALGALNHLGELTTSGRKMAELPVDPMLSKMILASEKYSCSEEI
  LTVAAMLSVNNSIFYRPKDKVVHADNARVNFFLPGGDHLVLLNVYTQWAESGYSSQWCYE
  NFVQFRSMRRARDVREQLEGLLERVEVGLSSCQGDYIRVRKAITAGYFYHTARLTRSGYR
  TVKQQQTVFIHPNSSLFEQQPRWLLYHELVLTTKEFMRQVLEIESSWLLEVAPHYYKAKE
  LEDPHAKKMPKKIGKTREELG
• Function: Required for pre-mRNA splicing as component of the spliceosome. Contributes to pre-mRNA splicing after spliceosome formation and prior to the first transesterification reaction. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Plays also a role in innate antiviral response by acting as a pattern recognition receptor sensing splicing signals in viral RNA. Mechanistically, TRIM6 promotes the interaction between unanchored 'Lys-48'-polyubiquitin chains and DHX16, leading to DHX16 interaction with RIGI and ssRNA to amplify RIGI-dependent innate antiviral immune responses.
• Tissue Specificity: Expressed in the spleen, thyroid and testis. Also expressed in the brain and cerebellum.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	DIS84UUI	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis type 4	DISSDHYG	Strong	Genetic Variation	[3]
Blindness	DISTIM10	Strong	Genetic Variation	[4]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[5]
Connective tissue disorder	DISKXBS3	Strong	Biomarker	[6]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[7]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[8]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Strong	Genetic Variation	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[9]
Neuromuscular disease and ocular or auditory anomalies with or without seizures	DISWVI1Q	Strong	Autosomal dominant	[10]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[11]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[6]
Werner syndrome	DISZY45W	Strong	Genetic Variation	[13]
Dilated cardiomyopathy	DISX608J	moderate	Genetic Variation	[14]
Systemic sclerosis	DISF44L6	moderate	Biomarker	[13]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[15]

5 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 Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[20]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[21]

4 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 Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (DHX16).	[24]

References

• [1] Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage.J Clin Neurosci. 2014 Sep;21(9):1627-31. doi: 10.1016/j.jocn.2013.11.048. Epub 2014 May 6.
• [2] Prp8 regulates oncogene-induced hyperplastic growth in Drosophila.Development. 2018 Nov 12;145(22):dev162156. doi: 10.1242/dev.162156.
• [3] DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. doi: 10.1086/421054. Epub 2004 Apr 21.
• [4] Prp8 retinitis pigmentosa mutants cause defects in the transition between the catalytic steps of splicing.RNA. 2016 May;22(5):793-809. doi: 10.1261/rna.055459.115. Epub 2016 Mar 11.
• [5] Vitamin D binding protein and the need for vitamin D in hemodialysis patients.J Ren Nutr. 2008 Sep;18(5):400-7. doi: 10.1053/j.jrn.2008.04.013.
• [6] Autoantibodies to a nucleolar RNA helicase protein in patients with connective tissue diseases.Arthritis Rheum. 1997 Aug;40(8):1487-92. doi: 10.1002/1529-0131(199708)40:8<1487::AID-ART18>3.0.CO;2-P.
• [7] Quantitative study of spongiform change in putamen of 24 cases of Creutzfeldt-Jakob disease.J Neuropathol Exp Neurol. 2004 Mar;63(3):193-8. doi: 10.1093/jnen/63.3.193.
• [8] Induction of cell-mediated immune responses in mice by DNA vaccines that express hepatitis C virus NS3 mutants lacking serine protease and NTPase/RNA helicase activities.PLoS One. 2014 Jun 5;9(6):e98877. doi: 10.1371/journal.pone.0098877. eCollection 2014.
• [9] Risk alleles for multiple sclerosis identified by a genomewide study.N Engl J Med. 2007 Aug 30;357(9):851-62. doi: 10.1056/NEJMoa073493. Epub 2007 Jul 29.
• [10] Paralog Studies Augment Gene Discovery: DDX and DHX Genes. Am J Hum Genet. 2019 Aug 1;105(2):302-316. doi: 10.1016/j.ajhg.2019.06.001. Epub 2019 Jun 27.
• [11] Retinitis Pigmentosa Mutations in Bad Response to Refrigeration 2 (Brr2) Impair ATPase and Helicase Activity.J Biol Chem. 2016 Jun 3;291(23):11954-65. doi: 10.1074/jbc.M115.710848. Epub 2016 Apr 12.
• [12] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [13] Werner's syndrome: from clinics to genetics.Clin Exp Rheumatol. 2000 Nov-Dec;18(6):760-6.
• [14] A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy.Eur Heart J. 2014 Apr;35(16):1069-77. doi: 10.1093/eurheartj/eht251. Epub 2013 Jul 12.
• [15] Inhibitory properties of the antibody response to Plasmodium vivax Duffy binding protein in an area with unstable malaria transmission.Scand J Immunol. 2008 Mar;67(3):270-8. doi: 10.1111/j.1365-3083.2007.02059.x. Epub 2008 Jan 22.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure. Environ Health Perspect. 2020 Jun;128(6):67015. doi: 10.1289/EHP6263. Epub 2020 Jun 30.
• [20] 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.
• [21] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [22] 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.
• [23] 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.
• [24] 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.