Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK1RYSK)

• DOT Name: Probable ATP-dependent RNA helicase DDX43 (DDX43)
• Synonyms: EC 3.6.4.13; Cancer/testis antigen 13; CT13; DEAD box protein 43; DEAD box protein HAGE; Helical antigen
• Gene Name: DDX43
• Related Disease:
  Advanced cancer
  Candidiasis
  Carcinoma
  Leukemia
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Testicular cancer
  Uveal Melanoma
  Melanoma
  Neoplasm
  Acute myelogenous leukaemia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Lactose intolerance
• UniProt ID: DDX43_HUMAN
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271 ; PF00013
• Sequence:
  MSHHGGAPKASTWVVASRRSSTVSRAPERRPAEELNRTGPEGYSVGRGGRWRGTSRPPEA
  VAAGHEELPLCFALKSHFVGAVIGRGGSKIKNIQSTTNTTIQIIQEQPESLVKIFGSKAM
  QTKAKAVIDNFVKKLEENYNSECGIDTAFQPSVGKDGSTDNNVVAGDRPLIDWDQIREEG
  LKWQKTKWADLPPIKKNFYKESTATSAMSKVEADSWRKENFNITWDDLKDGEKRPIPNPT
  CTFDDAFQCYPEVMENIKKAGFQKPTPIQSQAWPIVLQGIDLIGVAQTGTGKTLCYLMPG
  FIHLVLQPSLKGQRNRPGMLVLTPTRELALQVEGECCKYSYKGLRSVCVYGGGNRDEQIE
  ELKKGVDIIIATPGRLNDLQMSNFVNLKNITYLVLDEADKMLDMGFEPQIMKILLDVRPD
  RQTVMTSATWPHSVHRLAQSYLKEPMIVYVGTLDLVAVSSVKQNIIVTTEEEKWSHMQTF
  LQSMSSTDKVIVFVSRKAVADHLSSDLILGNISVESLHGDREQRDREKALENFKTGKVRI
  LIATDLASRGLDVHDVTHVYNFDFPRNIEEYVHRIGRTGRAGRTGVSITTLTRNDWRVAS
  ELINILERANQSIPEELVSMAERFKAHQQKREMERKMERPQGRPKKFH
• Tissue Specificity: Expressed in testis. Expressed in many tumors of various histological types at a level that is 100-fold higher than the level observed in normal tissues except testis.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Candidiasis	DISIRYMU	Strong	Genetic Variation	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Testicular cancer	DIS6HNYO	Strong	Altered Expression	[4]
Uveal Melanoma	DISA7ZGL	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	moderate	Biomarker	[7]
Neoplasm	DISZKGEW	Disputed	Biomarker	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Posttranslational Modification	[8]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Biomarker	[9]
Lactose intolerance	DISGENW9	Limited	Genetic Variation	[10]

4 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 Probable ATP-dependent RNA helicase DDX43 (DDX43).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Probable ATP-dependent RNA helicase DDX43 (DDX43).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Probable ATP-dependent RNA helicase DDX43 (DDX43).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Probable ATP-dependent RNA helicase DDX43 (DDX43).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Probable ATP-dependent RNA helicase DDX43 (DDX43).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Probable ATP-dependent RNA helicase DDX43 (DDX43).	[14]

References

• [1] DDX43 prefers single strand substrate and its full binding activity requires physical connection of all domains.Biochem Biophys Res Commun. 2019 Dec 10;520(3):594-599. doi: 10.1016/j.bbrc.2019.09.114. Epub 2019 Oct 14.
• [2] Multiple Candida strains in the course of a single systemic infection.J Clin Microbiol. 1988 Aug;26(8):1448-59. doi: 10.1128/jcm.26.8.1448-1459.1988.
• [3] SAGE mRNA expression in advanced-stage lung cancers.Eur J Surg Oncol. 2003 Dec;29(10):900-3. doi: 10.1016/j.ejso.2003.06.001.
• [4] Frequent expression of HAGE in presentation chronic myeloid leukaemias.Leukemia. 2002 Nov;16(11):2238-42. doi: 10.1038/sj.leu.2402732.
• [5] Exosomal miRNA Analysis in Non-small Cell Lung Cancer (NSCLC) Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool.J Vis Exp. 2016 May 27;(111):53900. doi: 10.3791/53900.
• [6] Overexpression of DDX43 mediates MEK inhibitor resistance through RAS Upregulation in uveal melanoma cells.Mol Cancer Ther. 2014 Aug;13(8):2073-80. doi: 10.1158/1535-7163.MCT-14-0095. Epub 2014 Jun 4.
• [7] The helicase HAGE prevents interferon--induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1.Cell Death Dis. 2014 Feb 13;5(2):e1061. doi: 10.1038/cddis.2014.29.
• [8] DDX43 promoter is frequently hypomethylated and may predict a favorable outcome in acute myeloid leukemia.Leuk Res. 2014 May;38(5):601-7. doi: 10.1016/j.leukres.2014.02.012. Epub 2014 Mar 3.
• [9] The methylation status of the DDX43 promoter in Chinese patients with chronic myeloid leukemia.Genet Test Mol Biomarkers. 2013 Jun;17(6):508-11. doi: 10.1089/gtmb.2012.0530. Epub 2013 Mar 15.
• [10] Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women.Eur J Clin Nutr. 2005 Oct;59(10):1105-11. doi: 10.1038/sj.ejcn.1602219.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] 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.
• [13] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [14] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.