Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHJANS0)

• DOT Name: Probable ATP-dependent RNA helicase DDX59 (DDX59)
• Synonyms: EC 3.6.4.13; DEAD box protein 59; Zinc finger HIT domain-containing protein 5
• Gene Name: DDX59
• Related Disease:
  Cleft palate
  Glioma
  Isolated cleft palate
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Orofaciodigital syndrome I
  Polydactyly
  Postaxial polydactyly
  Isolated congenital microcephaly
  Orofaciodigital syndrome
  Orofaciodigital syndrome V
• UniProt ID: DDX59_HUMAN
• PDB ID: 2YQP
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271 ; PF04438
• Sequence:
  MFVPRSLKIKRNANDDGKSCVAKIIKPDPEDLQLDKSRDVPVDAVATEAATIDRHISESC
  PFPSPGGQLAEVHSVSPEQGAKDSHPSEEPVKSFSKTQRWAEPGEPICVVCGRYGEYICD
  KTDEDVCSLECKAKHLLQVKEKEEKSKLSNPQKADSEPESPLNASYVYKEHPFILNLQED
  QIENLKQQLGILVQGQEVTRPIIDFEHCSLPEVLNHNLKKSGYEVPTPIQMQMIPVGLLG
  RDILASADTGSGKTAAFLLPVIMRALFESKTPSALILTPTRELAIQIERQAKELMSGLPR
  MKTVLLVGGLPLPPQLYRLQQHVKVIIATPGRLLDIIKQSSVELCGVKIVVVDEADTMLK
  MGFQQQVLDILENIPNDCQTILVSATIPTSIEQLASQLLHNPVRIITGEKNLPCANVRQI
  ILWVEDPAKKKKLFEILNDKKLFKPPVLVFVDCKLGADLLSEAVQKITGLKSISIHSEKS
  QIERKNILKGLLEGDYEVVVSTGVLGRGLDLISVRLVVNFDMPSSMDEYVHQIGRVGRLG
  QNGTAITFINNNSKRLFWDIAKRVKPTGSILPPQLLNSPYLHDQKRKEQQKDKQTQNDLV
  TGANLMDIIRKHDKSNSQK
• Tissue Specificity: Expressed in fibroblasts (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Orofaciodigital syndrome I	DIST27XL	Strong	Genetic Variation	[1]
Polydactyly	DIS25BMZ	Strong	Biomarker	[4]
Postaxial polydactyly	DIS085OV	Strong	Genetic Variation	[1]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[5]
Orofaciodigital syndrome	DISSB296	moderate	Genetic Variation	[1]
Orofaciodigital syndrome V	DIS8ZPZT	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Probable ATP-dependent RNA helicase DDX59 (DDX59).	[11]

References

• [1] Confirmation that mutations in DDX59 cause an autosomal recessive form of oral-facial-digital syndrome: Further delineation of the DDX59 phenotype in two new families.Eur J Med Genet. 2017 Oct;60(10):527-532. doi: 10.1016/j.ejmg.2017.07.009. Epub 2017 Jul 12.
• [2] MicroRNA-628-5p inhibits cell proliferation in glioma by targeting DDX59.J Cell Biochem. 2019 Oct;120(10):17293-17302. doi: 10.1002/jcb.28991. Epub 2019 May 20.
• [3] EGFR and Ras regulate DDX59 during lung cancer development.Gene. 2018 Feb 5;642:95-102. doi: 10.1016/j.gene.2017.11.029. Epub 2017 Nov 10.
• [4] Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome. Am J Hum Genet. 2013 Sep 5;93(3):555-60. doi: 10.1016/j.ajhg.2013.07.012. Epub 2013 Aug 22.
• [5] A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function.Hum Mutat. 2018 Feb;39(2):187-192. doi: 10.1002/humu.23368. Epub 2017 Nov 27.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.