Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5AAOQI)

• DOT Name: ATP-dependent RNA helicase A (DHX9)
• Synonyms: EC 3.6.4.13; DEAH box protein 9; DExH-box helicase 9; Leukophysin; LKP; Nuclear DNA helicase II; NDH II; RNA helicase A
• Gene Name: DHX9
• Related Disease:
  Lymphogranuloma venereum
  Breast neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Colitis
  Colorectal carcinoma
  Dermatomyositis
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Hepatitis B virus infection
  Hepatitis C virus infection
  Influenza
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malaria
  Matthew-Wood syndrome
  Mitochondrial disease
  Neoplasm
  Non-small-cell lung cancer
  Schizophrenia
  Small-cell lung cancer
  Systemic lupus erythematosus
  Tuberculosis
  Zika virus infection
  Werner syndrome
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Dengue
  Lymphoma
  Neuroblastoma
  Osteosarcoma
• UniProt ID: DHX9_HUMAN
• PDB ID: 3LLM; 3VYX; 3VYY; 8SZP
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00035 ; PF21010 ; PF04408 ; PF00271 ; PF07717
• Sequence:
  MGDVKNFLYAWCGKRKMTPSYEIRAVGNKNRQKFMCEVQVEGYNYTGMGNSTNKKDAQSN
  AARDFVNYLVRINEIKSEEVPAFGVASPPPLTDTPDTTANAEGDLPTTMGGPLPPHLALK
  AENNSEVGASGYGVPGPTWDRGANLKDYYSRKEEQEVQATLESEEVDLNAGLHGNWTLEN
  AKARLNQYFQKEKIQGEYKYTQVGPDHNRSFIAEMTIYIKQLGRRIFAREHGSNKKLAAQ
  SCALSLVRQLYHLGVVEAYSGLTKKKEGETVEPYKVNLSQDLEHQLQNIIQELNLEILPP
  PEDPSVPVALNIGKLAQFEPSQRQNQVGVVPWSPPQSNWNPWTSSNIDEGPLAFATPEQI
  SMDLKNELMYQLEQDHDLQAILQERELLPVKKFESEILEAISQNSVVIIRGATGCGKTTQ
  VPQFILDDFIQNDRAAECNIVVTQPRRISAVSVAERVAFERGEEPGKSCGYSVRFESILP
  RPHASIMFCTVGVLLRKLEAGIRGISHVIVDEIHERDINTDFLLVVLRDVVQAYPEVRIV
  LMSATIDTSMFCEYFFNCPIIEVYGRTYPVQEYFLEDCIQMTHFVPPPKDKKKKDKDDDG
  GEDDDANCNLICGDEYGPETRLSMSQLNEKETPFELIEALLKYIETLNVPGAVLVFLPGW
  NLIYTMQKHLEMNPHFGSHRYQILPLHSQIPREEQRKVFDPVPVGVTKVILSTNIAETSI
  TINDVVYVIDSCKQKVKLFTAHNNMTNYATVWASKTNLEQRKGRAGRVRPGFCFHLCSRA
  RFERLETHMTPEMFRTPLHEIALSIKLLRLGGIGQFLAKAIEPPPLDAVIEAEHTLRELD
  ALDANDELTPLGRILAKLPIEPRFGKMMIMGCIFYVGDAICTIAAATCFPEPFINEGKRL
  GYIHRNFAGNRFSDHVALLSVFQAWDDARMGGEEAEIRFCEHKRLNMATLRMTWEAKVQL
  KEILINSGFPEDCLLTQVFTNTGPDNNLDVVISLLAFGVYPNVCYHKEKRKILTTEGRNA
  LIHKSSVNCPFSSQDMKYPSPFFVFGEKIRTRAISAKGMTLVTPLQLLLFASKKVQSDGQ
  IVLVDDWIKLQISHEAAACITGLRAAMEALVVEVTKQPAIISQLDPVNERMLNMIRQISR
  PSAAGINLMIGSTRYGDGPRPPKMARYDNGSGYRRGGSSYSGGGYGGGYSSGGYGSGGYG
  GSANSFRAGYGAGVGGGYRGVSRGGFRGNSGGDYRGPSGGYRGSGGFQRGGGRGAYGTGY
  FGQGRGGGGY
• Function: Multifunctional ATP-dependent nucleic acid helicase that unwinds DNA and RNA in a 3' to 5' direction and that plays important roles in many processes, such as DNA replication, transcriptional activation, post-transcriptional RNA regulation, mRNA translation and RNA-mediated gene silencing. Requires a 3'-single-stranded tail as entry site for acid nuclei unwinding activities as well as the binding and hydrolyzing of any of the four ribo- or deoxyribo-nucleotide triphosphates (NTPs). Unwinds numerous nucleic acid substrates such as double-stranded (ds) DNA and RNA, DNA:RNA hybrids, DNA and RNA forks composed of either partially complementary DNA duplexes or DNA:RNA hybrids, respectively, and also DNA and RNA displacement loops (D- and R-loops), triplex-helical DNA (H-DNA) structure and DNA and RNA-based G-quadruplexes. Binds dsDNA, single-stranded DNA (ssDNA), dsRNA, ssRNA and poly(A)-containing RNA. Binds also to circular dsDNA or dsRNA of either linear and/or circular forms and stimulates the relaxation of supercoiled DNAs catalyzed by topoisomerase TOP2A. Plays a role in DNA replication at origins of replication and cell cycle progression. Plays a role as a transcriptional coactivator acting as a bridging factor between polymerase II holoenzyme and transcription factors or cofactors, such as BRCA1, CREBBP, RELA and SMN1. Binds to the CDKN2A promoter. Plays several roles in post-transcriptional regulation of gene expression. In cooperation with NUP98, promotes pre-mRNA alternative splicing activities of a subset of genes. As component of a large PER complex, is involved in the negative regulation of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms. Acts also as a nuclear resolvase that is able to bind and neutralize harmful massive secondary double-stranded RNA structures formed by inverted-repeat Alu retrotransposon elements that are inserted and transcribed as parts of genes during the process of gene transposition. Involved in the positive regulation of nuclear export of constitutive transport element (CTE)-containing unspliced mRNA. Component of the coding region determinant (CRD)-mediated complex that promotes cytoplasmic MYC mRNA stability. Plays a role in mRNA translation. Positively regulates translation of selected mRNAs through its binding to post-transcriptional control element (PCE) in the 5'-untranslated region (UTR). Involved with LARP6 in the translation stimulation of type I collagen mRNAs for CO1A1 and CO1A2 through binding of a specific stem-loop structure in their 5'-UTRs. Stimulates LIN28A-dependent mRNA translation probably by facilitating ribonucleoprotein remodeling during the process of translation. Plays also a role as a small interfering (siRNA)-loading factor involved in the RNA-induced silencing complex (RISC) loading complex (RLC) assembly, and hence functions in the RISC-mediated gene silencing process. Binds preferentially to short double-stranded RNA, such as those produced during rotavirus intestinal infection. This interaction may mediate NLRP9 inflammasome activation and trigger inflammatory response, including IL18 release and pyroptosis. Finally, mediates the attachment of heterogeneous nuclear ribonucleoproteins (hnRNPs) to actin filaments in the nucleus ; (Microbial infection) Plays a role in HIV-1 replication and virion infectivity. Enhances HIV-1 transcription by facilitating the binding of RNA polymerase II holoenzyme to the proviral DNA. Binds (via DRBM domain 2) to the HIV-1 TAR RNA and stimulates HIV-1 transcription of transactivation response element (TAR)-containing mRNAs. Involved also in HIV-1 mRNA splicing and transport. Positively regulates HIV-1 gag mRNA translation, through its binding to post-transcriptional control element (PCE) in the 5'-untranslated region (UTR). Binds (via DRBM domains) to a HIV-1 double-stranded RNA region of the primer binding site (PBS)-segment of the 5'-UTR, and hence stimulates DHX9 incorporation into virions and virion infectivity. Also plays a role as a cytosolic viral MyD88-dependent DNA and RNA sensors in plasmacytoid dendritic cells (pDCs), and hence induce antiviral innate immune responses. Binds (via the OB-fold region) to viral single-stranded DNA unmethylated C-phosphate-G (CpG) oligonucleotide.
• Reactome Pathway:
  DEx/H-box helicases activate type I IFN and inflammatory cytokines production (R-HSA-3134963)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  PKR-mediated signaling (R-HSA-9833482)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphogranuloma venereum	DIS0MMFT	Definitive	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[6]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Biomarker	[7]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Influenza	DIS3PNU3	Strong	Biomarker	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[12]
Malaria	DISQ9Y50	Strong	Biomarker	[13]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[14]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[6]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[18]
Zika virus infection	DISQUCTY	Strong	Biomarker	[19]
Werner syndrome	DISZY45W	moderate	Biomarker	[20]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[21]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[22]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[2]
Dengue	DISKH221	Limited	Biomarker	[19]
Lymphoma	DISN6V4S	Limited	Biomarker	[23]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[24]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[22]

3 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 ATP-dependent RNA helicase A (DHX9).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-dependent RNA helicase A (DHX9).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of ATP-dependent RNA helicase A (DHX9).	[39]

19 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 ATP-dependent RNA helicase A (DHX9).	[26]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-dependent RNA helicase A (DHX9).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent RNA helicase A (DHX9).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATP-dependent RNA helicase A (DHX9).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ATP-dependent RNA helicase A (DHX9).	[30]
Menadione	DMSJDTY	Approved	Menadione affects the expression of ATP-dependent RNA helicase A (DHX9).	[29]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of ATP-dependent RNA helicase A (DHX9).	[27]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of ATP-dependent RNA helicase A (DHX9).	[31]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of ATP-dependent RNA helicase A (DHX9).	[32]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of ATP-dependent RNA helicase A (DHX9).	[33]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of ATP-dependent RNA helicase A (DHX9).	[34]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of ATP-dependent RNA helicase A (DHX9).	[35]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of ATP-dependent RNA helicase A (DHX9).	[36]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of ATP-dependent RNA helicase A (DHX9).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of ATP-dependent RNA helicase A (DHX9).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent RNA helicase A (DHX9).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATP-dependent RNA helicase A (DHX9).	[42]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of ATP-dependent RNA helicase A (DHX9).	[43]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of ATP-dependent RNA helicase A (DHX9).	[44]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB increases the metabolism of ATP-dependent RNA helicase A (DHX9).	[37]

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