Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX3TTZH)

• DOT Name: Centrosomal protein of 63 kDa (CEP63)
• Synonyms: Cep63
• Gene Name: CEP63
• Related Disease:
  Advanced cancer
  Isolated congenital microcephaly
  Microlissencephaly
  Seckel syndrome 6
  Transitional cell carcinoma
  Autosomal recessive primary microcephaly
• UniProt ID: CEP63_HUMAN
• PDB ID: 6CSU; 6CSV; 7W91
• Pfam ID: PF17045
• Sequence:
  MEALLEGIQNRGHGGGFLTSCEAELQELMKQIDIMVAHKKSEWEGRTHALETCLKIREQE
  LKSLRSQLDVTHKEVGMLHQQVEEHEKIKQEMTMEYKQELKKLHEELCILKRSYEKLQKK
  QMREFRGNTKNHREDRSEIERLTAKIEEFRQKSLDWEKQRLIYQQQVSSLEAQRKALAEQ
  SEIIQAQLVNRKQKLESVELSSQSEIQHLSSKLERANDTICANELEIERLTMRVNDLVGT
  SMTVLQEQQQKEEKLRESEKLLEALQEEKRELKAALQSQENLIHEARIQKEKLQEKVKAT
  NTQHAVEAIRPREESLAEKKYTSQGQGDLDSVLSQLNFTHTSEDLLQAEVTCLEGSLESV
  SATCKQLSQELMEKYEELKRMEAHNNEYKAEIKKLKEQILQGEQSYSSALEGMKMEISHL
  TQELHQRDITIASTKGSSSDMEKRLRAEMQKAEDKAVEHKEILDQLESLKLENRHLSEMV
  MKLELGLHEAKEISLADLQENYIEALNKLVSENQQLQKDLMNTKSQLEISTQMCKKQNDR
  IFKPTHSRTTEFKNTEFKPTHGQHRHDGIKTEHYKTDLHSPRGQASDSINPMSRVLSPLS
  PQISPCSSTRSLTSYSLCKTHSLPSALDTNEANFSDTMSESMNDQEEFISSCSLPVSPLG
  SIATRFLEEEELRSHHILERLDAHIEELKRESEKTVRQFTALK
• Function: Required for normal spindle assembly. Plays a key role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication. Reported to be required for centrosomal recruitment of CEP152; however, this function has been questioned. Also recruits CDK1 to centrosomes. Plays a role in DNA damage response. Following DNA damage, such as double-strand breaks (DSBs), is removed from centrosomes; this leads to the inactivation of spindle assembly and delay in mitotic progression. Promotes stabilization of FXR1 protein by inhibiting FXR1 ubiquitination.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[2]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[3]
Seckel syndrome 6	DISASRUP	Strong	Autosomal recessive	[3]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[4]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[5]

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 Centrosomal protein of 63 kDa (CEP63).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Centrosomal protein of 63 kDa (CEP63).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centrosomal protein of 63 kDa (CEP63).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centrosomal protein of 63 kDa (CEP63).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centrosomal protein of 63 kDa (CEP63).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Centrosomal protein of 63 kDa (CEP63).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centrosomal protein of 63 kDa (CEP63).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Centrosomal protein of 63 kDa (CEP63).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Centrosomal protein of 63 kDa (CEP63).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Centrosomal protein of 63 kDa (CEP63).	[13]

References

• [1] Cep63 recruits Cdk1 to the centrosome: implications for regulation of mitotic entry, centrosome amplification, and genome maintenance.Cancer Res. 2011 Mar 15;71(6):2129-39. doi: 10.1158/0008-5472.CAN-10-2684.
• [2] CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.Nat Commun. 2015 Jul 9;6:7676. doi: 10.1038/ncomms8676.
• [3] A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet. 2011 Oct 9;43(11):1147-53. doi: 10.1038/ng.971.
• [4] The transcripts of SFRP1,CEP63 and EIF4G2 genes are frequently downregulated in transitional cell carcinomas of the bladder.Oncology. 2005;69(6):445-54. doi: 10.1159/000090984. Epub 2006 Jan 12.
• [5] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [6] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [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] 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.
• [14] 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.