Details of Drug Off-Target (DOT)

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

• DOT Name: DDB1- and CUL4-associated factor 17 (DCAF17)
• Gene Name: DCAF17
• Related Disease:
  Woodhouse-Sakati syndrome
  Alopecia
  Hypogonadism
  Neurodegeneration with brain iron accumulation
  Type-1/2 diabetes
  Deafness
  Deafness dystonia syndrome
  Hypotrichosis
  Intellectual disability
• UniProt ID: DCA17_HUMAN
• Pfam ID: PF15802
• Sequence:
  MGPTRKPNVCSRLSRRALGCFSRDAGVVQRTNLGILRALVCQESTKFKNVWTTHSRSPIA
  YERGRIYFDNYRRCVSSVASEPRKLYEMPKCSKSEKIEDALLWECPVGDILPNSSDYKSS
  LIALTAHNWLLRISATTGKILEKIYLAPYCKFRYLSWDTPQEVIAVKSAQNRGSAVARQA
  GIQQHVLLYLAVFRVLPFSLVGILEINKKIFGNVTDATLSHGILIVMYSSGLVRLYSFQT
  IAEQFMQQKLDLGCACRWGGTTGTVGEAPFGIPCNIKITDMPPLLFEVSSLENAFQIGGH
  PWHYIVTPNKKKQKGVFHICALKDNSLAKNGIQEMDCCSLESDWIYFHPDASGRIIHVGP
  NQVKVLKLTEIENNSSQHQISEDFVILANRENHKNENVLTVTASGRVVKKSFNLLDDDPE
  QETFKIVDYEDELDLLSVVAVTQIDAEGKAHLDFHCNEYGTLLKSIPLVESWDVTYSHEV
  YFDRDLVLHIEQKPNRVFSCYVYQMICDTGEEEETINRSC
• Function: May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Woodhouse-Sakati syndrome	DISHLVWB	Definitive	Autosomal recessive	[1]
Alopecia	DIS37HU4	Strong	CausalMutation	[2]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[3]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[5]
Deafness	DISKCLH4	Limited	CausalMutation	[2]
Deafness dystonia syndrome	DIS0480U	Limited	Genetic Variation	[6]
Hypotrichosis	DISSW933	Limited	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DDB1- and CUL4-associated factor 17 (DCAF17).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome.Clin Genet. 2016 Sep;90(3):263-9. doi: 10.1111/cge.12700. Epub 2016 Jan 19.
• [3] A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature.J Pediatr Endocrinol Metab. 2019 Nov 26;32(11):1287-1293. doi: 10.1515/jpem-2019-0173.
• [4] Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.Neuropathol Appl Neurobiol. 2016 Apr;42(3):220-41. doi: 10.1111/nan.12242. Epub 2015 Jun 2.
• [5] Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008 Dec;83(6):684-91. doi: 10.1016/j.ajhg.2008.10.018. Epub 2008 Nov 20.
• [6] The syndrome of deafness-dystonia: clinical and genetic heterogeneity.Mov Disord. 2013 Jun;28(6):795-803. doi: 10.1002/mds.25394. Epub 2013 Feb 15.
• [7] Alopecia and hypotrichosis as characteristic findings in Woodhouse-Sakati syndrome: report of a family with mutation in the C2orf37 gene.Pediatr Dermatol. 2014 Jan-Feb;31(1):83-7. doi: 10.1111/pde.12219. Epub 2013 Sep 9.
• [8] A patient with five chromosomal rearrangements and a 2q31.1 microdeletion.Clin Chim Acta. 2014 Mar 20;430:129-33. doi: 10.1016/j.cca.2014.01.002. Epub 2014 Jan 9.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] 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.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.