Details of Drug Off-Target (DOT)

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

• DOT Name: Dynein axonemal assembly factor 4 (DNAAF4)
• Synonyms: Dyslexia susceptibility 1 candidate gene 1 protein
• Gene Name: DNAAF4
• Related Disease:
  Advanced cancer
  Autism
  Breast cancer
  Breast carcinoma
  Ciliopathy
  Male infertility
  Primary ciliary dyskinesia 1
  Primary ciliary dyskinesia 25
  Chronic obstructive pulmonary disease
  Neoplasm
  Primary ciliary dyskinesia
  Colorectal carcinoma
  Nervous system disease
  Neuroblastoma
• UniProt ID: DAAF4_HUMAN
• Pfam ID: PF04969
• Sequence:
  MPLQVSDYSWQQTKTAVFLSLPLKGVCVRDTDVFCTENYLKVNFPPFLFEAFLYAPIDDE
  SSKAKIGNDTIVFTLYKKEAAMWETLSVTGVDKEMMQRIREKSILQAQERAKEATEAKAA
  AKREDQKYALSVMMKIEEEERKKIEDMKENERIKATKALEAWKEYQRKAEEQKKIQREEK
  LCQKEKQIKEERKKIKYKSLTRNLASRNLAPKGRNSENIFTEKLKEDSIPAPRSVGSIKI
  NFTPRVFPTALRESQVAEEEEWLHKQAEARRAMNTDIAELCDLKEEEKNPEWLKDKGNKL
  FATENYLAAINAYNLAIRLNNKMPLLYLNRAACHLKLKNLHKAIEDSSKALELLMPPVTD
  NANARMKAHVRRGTAFCQLELYVEGLQDYEAALKIDPSNKIVQIDAEKIRNVIQGTELKS
• Function: Axonemal dynein assembly factor required for ciliary motility. Involved in neuronal migration during development of the cerebral neocortex. May regulate the stability and proteasomal degradation of the estrogen receptors that play an important role in neuronal differentiation, survival and plasticity.
• Tissue Specificity: Expressed in several tissues, including brain, lung, kidney and testis. In brain localizes to a fraction of cortical neurons and white matter glial cells.

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	Altered Expression	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[3]
Male infertility	DISY3YZZ	Strong	Biomarker	[4]
Primary ciliary dyskinesia 1	DISPGX6H	Strong	Biomarker	[4]
Primary ciliary dyskinesia 25	DIS4MDWP	Strong	Autosomal recessive	[4]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[4]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[5]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[6]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dynein axonemal assembly factor 4 (DNAAF4).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dynein axonemal assembly factor 4 (DNAAF4).	[16]

References

• [1] The dyslexia candidate gene DYX1C1 is a potential marker of poor survival in breast cancer.BMC Cancer. 2012 Feb 29;12:79. doi: 10.1186/1471-2407-12-79.
• [2] Family-based association study of DYX1C1 variants in autism.Eur J Hum Genet. 2005 Jan;13(1):127-30. doi: 10.1038/sj.ejhg.5201272.
• [3] Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs.FASEB J. 2016 Oct;30(10):3578-3587. doi: 10.1096/fj.201500124RR. Epub 2016 Jul 22.
• [4] DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet. 2013 Sep;45(9):995-1003. doi: 10.1038/ng.2707. Epub 2013 Jul 21.
• [5] Molecular characterization of the DYX1C1 gene and its application as a cancer biomarker.J Cancer Res Clin Oncol. 2009 Feb;135(2):265-70. doi: 10.1007/s00432-008-0445-8. Epub 2008 Jul 10.
• [6] Exploring the transcriptome of ciliated cells using in silico dissection of human tissues.PLoS One. 2012;7(4):e35618. doi: 10.1371/journal.pone.0035618. Epub 2012 Apr 25.
• [7] The rs3743205 SNP is important for the regulation of the dyslexia candidate gene DYX1C1 by estrogen receptor and DNA methylation.Mol Endocrinol. 2012 Apr;26(4):619-29. doi: 10.1210/me.2011-1376. Epub 2012 Mar 1.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [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] 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.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.