Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6PF80T)

• DOT Name: Centrosomal protein of 131 kDa (CEP131)
• Synonyms: 5-azacytidine-induced protein 1; Pre-acrosome localization protein 1
• Gene Name: CEP131
• Related Disease:
  Bardet biedl syndrome
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Frontotemporal dementia
  Hepatocellular carcinoma
  Male infertility
  Zika virus infection
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Advanced cancer
  Neoplasm
• UniProt ID: CP131_HUMAN
• Sequence:
  MKGTRAIGSVPERSPAGVDLSLTGLPPPVSRRPGSAATTKPIVRSVSVVTGSEQKRKVLE
  ATGPGGSQAINNLRRSNSTTQVSQPRSGSPRPTEPTDFLMLFEGSPSGKKRPASLSTAPS
  EKGATWNVLDDQPRGFTLPSNARSSSALDSPAGPRRKECTVALAPNFTANNRSNKGAVGN
  CVTTMVHNRYTPSERAPPLKSSNQTAPSLNNIIKAATCEGSESSGFGKLPKNVSSATHSA
  RNNTGGSTGLPRRKEVTEEEAERFIHQVNQATVTIQRWYRHQVQRRGAGAARLEHLLQAK
  REEQRQRSGEGTLLDLHQQKEAARRKAREEKARQARRAAIQELQQKRALRAQKASTAERG
  PPENPRETRVPGMRQPAQELSPTPGGTAHQALKANNTGGGLPAAGPGDRCLPTSDSSPEP
  QQPPEDRTQDVLAQDAAGDNLEMMAPSRGSAKSRGPLEELLHTLQLLEKEPDVLPRPRTH
  HRGRYAWASEVTTEDDASSLTADNLEKFGKLSAFPEPPEDGTLLSEAKLQSIMSFLDEME
  KSGQDQLDSQQEGWVPEAGPGPLELGSEVSTSVMRLKLEVEEKKQAMLLLQRALAQQRDL
  TARRVKETEKALSRQLQRQREHYEATIQRHLAFIDQLIEDKKVLSEKCEAVVAELKQEDQ
  RCTERVAQAQAQHELEIKKLKELMSATEKARREKWISEKTKKIKEVTVRGLEPEIQKLIA
  RHKQEVRRLKSLHEAELLQSDERASQRCLRQAEELREQLEREKEALGQQERERARQRFQQ
  HLEQEQWALQQQRQRLYSEVAEERERLGQQAARQRAELEELRQQLEESSSALTRALRAEF
  EKGREEQERRHQMELNTLKQQLELERQAWEAGRTRKEEAWLLNREQELREEIRKGRDKEI
  ELVIHRLEADMALAKEESEKAAESRIKRLRDKYEAELSELEQSERKLQERCSELKGQLGE
  AEGENLRLQGLVRQKERALEDAQAVNEQLSSERSNLAQVIRQEFEDRLAASEEETRQAKA
  ELATLQARQQLELEEVHRRVKTALARKEEAVSSLRTQHEAAVKRADHLEELLEQHRRPTP
  STK
• Function: Component of centriolar satellites contributing to the building of a complex and dynamic network required to regulate cilia/flagellum formation. In proliferating cells, MIB1-mediated ubiquitination induces its sequestration within centriolar satellites, precluding untimely cilia formation initiation. In contrast, during normal and ultraviolet or heat shock cellular stress-induced ciliogenesis, its non-ubiquitinated form is rapidly displaced from centriolar satellites and recruited to centrosome/basal bodies in a microtubule- and p38 MAPK-dependent manner. Acts also as a negative regulator of BBSome ciliary trafficking. Plays a role in sperm flagellar formation; may be involved in the regulation of intraflagellar transport (IFT) and/or intramanchette (IMT) trafficking, which are important for axoneme extension and/or cargo delivery to the nascent sperm tail. Required for optimal cell proliferation and cell cycle progression; may play a role in the regulation of genome stability in non-ciliogenic cells. Involved in centriole duplication. Required for CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2. Essential for maintaining proper centriolar satellite integrity.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Male infertility	DISY3YZZ	Strong	Biomarker	[7]
Zika virus infection	DISQUCTY	Strong	Biomarker	[8]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Moderate	Autosomal recessive	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Centrosomal protein of 131 kDa (CEP131).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Centrosomal protein of 131 kDa (CEP131).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Centrosomal protein of 131 kDa (CEP131).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Centrosomal protein of 131 kDa (CEP131).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Centrosomal protein of 131 kDa (CEP131).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Centrosomal protein of 131 kDa (CEP131).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Centrosomal protein of 131 kDa (CEP131).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Centrosomal protein of 131 kDa (CEP131).	[13]

References

• [1] The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.PLoS Genet. 2014 Feb 13;10(2):e1004083. doi: 10.1371/journal.pgen.1004083. eCollection 2014 Feb.
• [2] USP9X regulates centrosome duplication and promotes breast carcinogenesis.Nat Commun. 2017 Mar 31;8:14866. doi: 10.1038/ncomms14866.
• [3] Enhanced anticancer effects of a methylation inhibitor by inhibiting a novel DNMT1 target, CEP 131, in cervical cancer.BMB Rep. 2019 May;52(5):342-347. doi: 10.5483/BMBRep.2019.52.5.055.
• [4] Cep131 overexpression promotes centrosome amplification and colon cancer progression by regulating Plk4 stability.Cell Death Dis. 2019 Jul 29;10(8):570. doi: 10.1038/s41419-019-1778-8.
• [5] A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.Neurobiol Aging. 2015 Oct;36(10):2904.e13-26. doi: 10.1016/j.neurobiolaging.2015.06.005. Epub 2015 Jun 12.
• [6] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [7] Acute versus chronic loss of mammalian Azi1/Cep131 results in distinct ciliary phenotypes.PLoS Genet. 2013;9(12):e1003928. doi: 10.1371/journal.pgen.1003928. Epub 2013 Dec 26.
• [8] Zika virus increases mind bomb 1 levels, causing degradation of pericentriolar material 1 (PCM1) and dispersion of PCM1-containing granules from the centrosome.J Biol Chem. 2019 Dec 6;294(49):18742-18755. doi: 10.1074/jbc.RA119.010973. Epub 2019 Oct 30.
• [9] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [10] CEP131 indicates poor prognosis and promotes cell proliferation and migration in hepatocellular carcinoma.Int J Biochem Cell Biol. 2017 Sep;90:1-8. doi: 10.1016/j.biocel.2017.07.001. Epub 2017 Jul 8.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.