Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM1A5KP)

• DOT Name: Probable ATP-dependent RNA helicase DHX37 (DHX37)
• Synonyms: EC 3.6.4.13; DEAH box protein 37
• Gene Name: DHX37
• Related Disease:
  46,XY disorder of sex development
  46,XY sex reversal 11
  Chronic granulomatous disease
  Gonadal dysgenesis
  Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies
  Triple negative breast cancer
  Turner syndrome
  Isolated congenital microcephaly
  46,XY complete gonadal dysgenesis
  46,XY partial gonadal dysgenesis
  Obsolete testicular regression syndrome
• UniProt ID: DHX37_HUMAN
• PDB ID: 7MQA
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF21010 ; PF04408 ; PF00271 ; PF07717
• Sequence:
  MGKLRRRYNIKGRQQAGPGPSKGPPEPPPVQLELEDKDTLKGVDASNALVLPGKKKKKTK
  APPLSKKEKKPLTKKEKKVLQKILEQKEKKSQRAEMLQKLSEVQASEAEMRLFYTTSKLG
  TGNRMYHTKEKADEVVAPGQEKISSLSGAHRKRRRWPSAEEEEEEEEESESELEEESELD
  EDPAAEPAEAGVGTTVAPLPPAPAPSSQPVPAGMTVPPPPAAAPPLPRALAKPAVFIPVN
  RSPEMQEERLKLPILSEEQVIMEAVAEHPIVIVCGETGSGKTTQVPQFLYEAGFSSEDSI
  IGVTEPRRVAAVAMSQRVAKEMNLSQRVVSYQIRYEGNVTEETRIKFMTDGVLLKEIQKD
  FLLLRYKVVIIDEAHERSVYTDILIGLLSRIVTLRAKRNLPLKLLIMSATLRVEDFTQNP
  RLFAKPPPVIKVESRQFPVTVHFNKRTPLEDYSGECFRKVCKIHRMLPAGGILVFLTGQA
  EVHALCRRLRKAFPPSRARPQEKDDDQKDSVEEMRKFKKSRARAKKARAEVLPQINLDHY
  SVLPAGEGDEDREAEVDEEEGALDSDLDLDLGDGGQDGGEQPDASLPLHVLPLYSLLAPE
  KQAQVFKPPPEGTRLCVVATNVAETSLTIPGIKYVVDCGKVKKRYYDRVTGVSSFRVTWV
  SQASADQRAGRAGRTEPGHCYRLYSSAVFGDFEQFPPPEITRRPVEDLILQMKALNVEKV
  INFPFPTPPSVEALLAAEELLIALGALQPPQKAERVKQLQENRLSCPITALGRTMATFPV
  APRYAKMLALSRQHGCLPYAITIVASMTVRELFEELDRPAASDEELTRLKSKRARVAQMK
  RTWAGQGASLKLGDLMVLLGAVGACEYASCTPQFCEANGLRYKAMMEIRRLRGQLTTAVN
  AVCPEAELFVDPKMQPPTESQVTYLRQIVTAGLGDHLARRVQSEEMLEDKWRNAYKTPLL
  DDPVFIHPSSVLFKELPEFVVYQEIVETTKMYMKGVSSVEVQWIPALLPSYCQFDKPLEE
  PAPTYCPERGRVLCHRASVFYRVGWPLPAIEVDFPEGIDRYKHFARFLLEGQVFRKLASY
  RSCLLSSPGTMLKTWARLQPRTESLLRALVAEKADCHEALLAAWKKNPKYLLAEYCEWLP
  QAMHPDIEKAWPPTTVH
• Function: ATP-binding RNA helicase that plays a role in maturation of the small ribosomal subunit in ribosome biogenesis. Required for the release of the U3 snoRNP from pre-ribosomal particles. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Plays a role in early testis development. Probably also plays a role in brain development.
• Tissue Specificity: Expressed in the fallopian tube, ovary, uterus and testis. Also expressed in the brain.
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY disorder of sex development	DIS78CGG	Strong	Genetic Variation	[1]
46,XY sex reversal 11	DISYJTLT	Strong	Autosomal dominant	[2]
Chronic granulomatous disease	DIS9ZR24	Strong	Biomarker	[3]
Gonadal dysgenesis	DISIL2ZI	Strong	Genetic Variation	[1]
Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies	DISMSS9S	Strong	Autosomal recessive	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[5]
Turner syndrome	DIS2035C	Strong	Genetic Variation	[1]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[6]
46,XY complete gonadal dysgenesis	DISLF3LT	Supportive	Autosomal dominant	[1]
46,XY partial gonadal dysgenesis	DISMNH0C	Supportive	Autosomal dominant	[1]
Obsolete testicular regression syndrome	DIS0HKI2	Supportive	Autosomal recessive	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Probable ATP-dependent RNA helicase DHX37 (DHX37) affects the response to substance of DTI-015.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[9]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[9]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[9]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Probable ATP-dependent RNA helicase DHX37 (DHX37).	[15]

References

• [1] Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome. Genet Med. 2020 Jan;22(1):150-159. doi: 10.1038/s41436-019-0606-y. Epub 2019 Jul 24.
• [2] 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.
• [3] Clinical and molecular findings of chronic granulomatous disease in Oman: family studies.Clin Genet. 2015 Feb;87(2):185-9. doi: 10.1111/cge.12351. Epub 2014 Feb 17.
• [4] Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron. 2015 Nov 4;88(3):499-513. doi: 10.1016/j.neuron.2015.09.048.
• [5] Systematic Immunotherapy Target Discovery Using Genome-Scale InVivo CRISPR Screens in CD8T Cells.Cell. 2019 Aug 22;178(5):1189-1204.e23. doi: 10.1016/j.cell.2019.07.044.
• [6] The DEAH-box RNA helicase Dhr1 contains a remarkable carboxyl terminal domain essential for small ribosomal subunit biogenesis.Nucleic Acids Res. 2019 Aug 22;47(14):7548-7563. doi: 10.1093/nar/gkz529.
• [7] Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum. J Clin Endocrinol Metab. 2019 Dec 1;104(12):5923-5934. doi: 10.1210/jc.2019-00984.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] 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.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] 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.
• [18] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.