Details of Drug Off-Target (DOT)

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

• DOT Name: Centrosomal protein of 164 kDa (CEP164)
• Synonyms: Cep164
• Gene Name: CEP164
• Related Disease:
  Ciliopathy
  Nephronophthisis 15
  Autosomal recessive polycystic kidney disease
  Bardet biedl syndrome
  Xeroderma pigmentosum group A
  Senior-Loken syndrome
  Advanced cancer
  Nephronophthisis
  Rhabdomyosarcoma
• UniProt ID: CE164_HUMAN
• PDB ID: 7NWJ; 7O06; 7O0S; 7O3B
• Sequence:
  MAGRPLRIGDQLVLEEDYDETYIPSEQEILEFAREIGIDPIKEPELMWLAREGIVAPLPG
  EWKPCQDITGDIYYFNFANGQSMWDHPCDEHYRSLVIQERAKLSTSGAIKKKKKKKEKKD
  KKDRDPPKSSLALGSSLAPVHVPLGGLAPLRGLVDTPPSALRGSQSVSLGSSVESGRQLG
  ELMLPSQGLKTSAYTKGLLGSIYEDKTALSLLGLGEETNEEDEEESDNQSVHSSSEPLRN
  LHLDIGALGGDFEYEESLRTSQPEEKKDVSLDSDAAGPPTPCKPSSPGADSSLSSAVGKG
  RQGSGARPGLPEKEENEKSEPKICRNLVTPKADPTGSEPAKASEKEAPEDTVDAGEEGSR
  REEAAKEPKKKASALEEGSSDASQELEISEHMKEPQLSDSIASDPKSFHGLDFGFRSRIS
  EHLLDVDVLSPVLGGACRQAQQPLGIEDKDDSQSSQDELQSKQSKGLEERLSPPLPHEER
  AQSPPRSLATEEEPPQGPEGQPEWKEAEELGEDSAASLSLQLSLQREQAPSPPAACEKGK
  EQHSQAEELGPGQEEAEDPEEKVAVSPTPPVSPEVRSTEPVAPPEQLSEAALKAMEEAVA
  QVLEQDQRHLLESKQEKMQQLREKLCQEEEEEILRLHQQKEQSLSSLRERLQKAIEEEEA
  RMREEESQRLSWLRAQVQSSTQADEDQIRAEQEASLQKLREELESQQKAERASLEQKNRQ
  MLEQLKEEIEASEKSEQAALNAAKEKALQQLREQLEGERKEAVATLEKEHSAELERLCSS
  LEAKHREVVSSLQKKIQEAQQKEEAQLQKCLGQVEHRVHQKSYHVAGYEHELSSLLREKR
  QEVEGEHERRLDKMKEEHQQVMAKAREQYEAEERKQRAELLGHLTGELERLQRAHERELE
  TVRQEQHKRLEDLRRRHREQERKLQDLELDLETRAKDVKARLALLEVQEETARREKQQLL
  DVQRQVALKSEEATATHQQLEEAQKEHTHLLQSNQQLREILDELQARKLKLESQVDLLQA
  QSQQLQKHFSSLEAEAQKKQHLLREVTVEENNASPHFEPDLHIEDLRKSLGTNQTKEVSS
  SLSQSKEDLYLDSLSSHNVWHLLSAEGVALRSAKEFLVQQTRSMRRRQTALKAAQQHWRH
  ELASAQEVAKDPPGIKALEDMRKNLEKETRHLDEMKSAMRKGHNLLKKKEEKLNQLESSL
  WEEASDEGTLGGSPTKKAVTFDLSDMDSLSSESSESFSPPHREWWRQQRIDSTPSLTSRK
  IHGLSHSLRQISSQLSSVLSILDSLNPQSPPPLLASMPAQLPPRDPKSTPTPTYYGSLAR
  FSALSSATPTSTQWAWDSGQGPRLPSSVAQTVDDFLLEKWRKYFPSGIPLLSNSPTPLES
  RLGYMSASEQLRLLQHSHSQVPEAGSTTFQGIIEANRRWLERVKNDPRLPLFSSTPKPKA
  TLSLLQLGLDEHNRVKVYRF
• Function: Plays a role in microtubule organization and/or maintenance for the formation of primary cilia (PC), a microtubule-based structure that protrudes from the surface of epithelial cells. Plays a critical role in G2/M checkpoint and nuclear divisions. A key player in the DNA damage-activated ATR/ATM signaling cascade since it is required for the proper phosphorylation of H2AX, RPA, CHEK2 and CHEK1. Plays a critical role in chromosome segregation, acting as a mediator required for the maintenance of genomic stability through modulation of MDC1, RPA and CHEK1.
• Tissue Specificity: Expressed in several cell lines.
• 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Nephronophthisis 15	DISQH0WC	Definitive	Autosomal recessive	[2]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[3]
Bardet biedl syndrome	DISTBNZW	Strong	Genetic Variation	[2]
Xeroderma pigmentosum group A	DIS38HWC	Strong	Biomarker	[4]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[5]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[6]
Nephronophthisis	DISXU4HY	Limited	Biomarker	[3]
Rhabdomyosarcoma	DISNR7MS	Limited	Biomarker	[6]

6 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 Centrosomal protein of 164 kDa (CEP164).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centrosomal protein of 164 kDa (CEP164).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Centrosomal protein of 164 kDa (CEP164).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Centrosomal protein of 164 kDa (CEP164).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the expression of Centrosomal protein of 164 kDa (CEP164).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Centrosomal protein of 164 kDa (CEP164).	[13]

3 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 164 kDa (CEP164).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Centrosomal protein of 164 kDa (CEP164).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Centrosomal protein of 164 kDa (CEP164).	[15]

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] Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum. Sci Rep. 2016 Oct 6;6:34764. doi: 10.1038/srep34764.
• [3] Nephronophthisis-associated CEP164 regulates cell cycle progression, apoptosis and epithelial-to-mesenchymal transition.PLoS Genet. 2014 Oct 23;10(10):e1004594. doi: 10.1371/journal.pgen.1004594. eCollection 2014 Oct.
• [4] UV-dependent interaction between Cep164 and XPA mediates localization of Cep164 at sites of DNA damage and UV sensitivity.Cell Cycle. 2009 Feb 15;8(4):655-64. doi: 10.4161/cc.8.4.7844. Epub 2009 Feb 14.
• [5] Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012 Aug 3;150(3):533-48. doi: 10.1016/j.cell.2012.06.028.
• [6] Inhibition of centrosomal protein 164 sensitizes rhabdomyosarcoma cells to radiotherapy.Exp Ther Med. 2017 May;13(5):2311-2315. doi: 10.3892/etm.2017.4281. Epub 2017 Mar 29.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [13] 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.
• [14] 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.
• [15] 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.