Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOKZR9B)

• DOT Name: Centrosomal protein of 152 kDa (CEP152)
• Synonyms: Cep152
• Gene Name: CEP152
• Related Disease:
  Microcephaly 4, primary, autosomal recessive
  Microcephaly with or without short stature
  Microcephaly 9, primary, autosomal recessive
  Seckel syndrome 1
  Advanced cancer
  leukaemia
  Leukemia
  Autosomal recessive primary microcephaly
  Seckel syndrome
• UniProt ID: CE152_HUMAN
• PDB ID: 4N7V; 6CSU; 6CSV
• Sequence:
  MSLDFGSVALPVQNEDEEYDEEDYEREKELQQLLTDLPHDMLDDDLSSPELQYSDCSEDG
  TDGQPHHPEQLEMSWNEQMLPKSQSVNGYNEIQSLYAGEKCGNVWEENRSKTEDRHPVYH
  PEEGGDEGGSGYSPPSKCEQTDLYHLPENFRPYTNGQKQEFNNQATNVIKFSDPQWNHFQ
  GPSCQGLEPYNKVTYKPYQSSAQNNGSPAQEITGSDTFEGLQQQFLGANENSAENMQIIQ
  LQVLNKAKERQLENLIEKLNESERQIRYLNHQLVIIKDEKDGLTLSLRESQKLFQNGKER
  EIQLEAQIKALETQIQALKVNEEQMIKKSRTTEMALESLKQQLVDLHHSESLQRAREQHE
  SIVMGLTKKYEEQVLSLQKNLDATVTALKEQEDICSRLKDHVKQLERNQEAIKLEKTEII
  NKLTRSLEESQKQCAHLLQSGSVQEVAQLQFQLQQAQKAHAMSANMNKALQEELTELKDE
  ISLYESAAKLGIHPSDSEGELNIELTESYVDLGIKKVNWKKSKVTSIVQEEDPNEELSKD
  EFILKLKAEVQRLLGSNSMKRHLVSQLQNDLKDCHKKIEDLHQVKKDEKSIEVETKTDTS
  EKPKNQLWPESSTSDVVRDDILLLKNEIQVLQQQNQELKETEGKLRNTNQDLCNQMRQMV
  QDFDHDKQEAVDRCERTYQQHHEAMKTQIRESLLAKHALEKQQLFEAYERTHLQLRSELD
  KLNKEVTAVQECYLEVCREKDNLELTLRKTTEKEQQTQEKIKEKLIQQLEKEWQSKLDQT
  IKAMKKKTLDCGSQTDQVTTSDVISKKEMAIMIEEQKCTIQQNLEQEKDIAIKGAMKKLE
  IELELKHCENITKQVEIAVQNAHQRWLGELPELAEYQALVKAEQKKWEEQHEVSVNKRIS
  FAVSEAKEKWKSELENMRKNILPGKELEEKIHSLQKELELKNEEVPVVIRAELAKARSEW
  NKEKQEEIHRIQEQNEQDYRQFLDDHRNKINEVLAAAKEDFMKQKTELLLQKETELQTCL
  DQSRREWTMQEAKRIQLEIYQYEEDILTVLGVLLSDTQKEHISDSEDKQLLEIMSTCSSK
  WMSVQYFEKLKGCIQKAFQDTLPLLVENADPEWKKRNMAELSKDSASQGTGQGDPGPAAG
  HHAQPLALQATEAEADKKKVLEIKDLCCGHCFQELEKAKQECQDLKGKLEKCCRHLQHLE
  RKHKAVVEKIGEENNKVVEELIEENNDMKNKLEELQTLCKTPPRSLSAGAIENACLPCSG
  GALEELRGQYIKAVKKIKCDMLRYIQESKERAAEMVKAEVLRERQETARKMRKYYLICLQ
  QILQDDGKEGAEKKIMNAASKLATMAKLLETPISSKSQSKTTQSALPLTSEMLIAVKKSK
  RNDVNQKIPCCIESKSNSVNTITRTLCEQAPKRRAACNLQRLLENSEHQSIKHVGSKETH
  LEFQFGDGSCKHLNSLPRNVSPEFVPCEGEGGFGLHKKKDLLSDNGSESLPHSAAYPFLG
  TLGNKPSPRCTPGPSESGCMHITFRDSNERLGLKVYKCNPLMESENAASEKSQGLDVQEP
  PVKDGGDLSDCLGWPSSSATLSFDSREASFVHGRPQGTLEIPSESVKSKQFSPSGYLSDT
  EESNMICQTMKCQRYQTPYLSEETTYLEPGKISVNCGHPSRHKADRLKSDFKKLSSTLPS
  SVCQQPSRKLIVPLSSQQDSGFDSPFVNLD
• Function: Necessary for centrosome duplication; the function seems also to involve CEP63, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication. Acts as a molecular scaffold facilitating the interaction of PLK4 and CENPJ, 2 molecules involved in centriole formation. Proposed to snatch PLK4 away from PLK4:CEP92 complexes in early G1 daughter centriole and to reposition PLK4 at the outer boundary of a newly forming CEP152 ring structure. Also plays a key role in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Overexpression of CEP152 can drive amplification of centrioles.
• 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
Microcephaly 4, primary, autosomal recessive	DIS4HVZ0	Definitive	Autosomal recessive	[1]
Microcephaly with or without short stature	DISZ36SN	Definitive	Autosomal recessive	[2]
Microcephaly 9, primary, autosomal recessive	DISIO2Q0	Strong	Autosomal recessive	[3]
Seckel syndrome 1	DISLNT6G	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[4]
leukaemia	DISS7D1V	moderate	Biomarker	[5]
Leukemia	DISNAKFL	moderate	Biomarker	[5]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[6]
Seckel syndrome	DISEVUBA	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Centrosomal protein of 152 kDa (CEP152).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centrosomal protein of 152 kDa (CEP152).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Centrosomal protein of 152 kDa (CEP152).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Centrosomal protein of 152 kDa (CEP152).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Centrosomal protein of 152 kDa (CEP152).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Centrosomal protein of 152 kDa (CEP152).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centrosomal protein of 152 kDa (CEP152).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Centrosomal protein of 152 kDa (CEP152).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centrosomal protein of 152 kDa (CEP152).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Centrosomal protein of 152 kDa (CEP152).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Centrosomal protein of 152 kDa (CEP152).	[21]

References

• [1] CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet. 2011 Jan;43(1):23-6. doi: 10.1038/ng.725. Epub 2010 Dec 5.
• [2] 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.
• [3] Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am J Hum Genet. 2010 Jul 9;87(1):40-51. doi: 10.1016/j.ajhg.2010.06.003.
• [4] Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis.Nat Struct Mol Biol. 2014 Aug;21(8):696-703. doi: 10.1038/nsmb.2846. Epub 2014 Jun 29.
• [5] D40/KNL1/CASC5 and autosomal recessive primary microcephaly.Congenit Anom (Kyoto). 2017 Nov;57(6):191-196. doi: 10.1111/cga.12252. Epub 2017 Nov 1.
• [6] 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.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] 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.
• [18] 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.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.