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The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity

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dc.creatorGordillo, Miriamspa
dc.creatorVega, Hugospa
dc.creatorTrainer, Alison H.spa
dc.creatorHou, Fajianspa
dc.creatorSakai, Noriospa
dc.creatorLuque Bernal, Ricardo Miguel
dc.date.accessioned2020-08-19T14:40:58Z
dc.date.available2020-08-19T14:40:58Z
dc.date.created2008-04-14spa
dc.description.abstractRoberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion. We identified 10 new mutations expanding the number to 26 known ESCO2 mutations. We observed that these mutations result in complete or partial loss of the acetyltransferase domain except for the only missense mutation that occurs in this domain (c.1615T>G, W539G). To investigate the mechanism underlying RBS, we analyzed ESCO2 mutations for their effect on enzymatic activity and cellular phenotype. We found that ESCO2 W539G results in loss of autoacetyltransferase activity. The cellular phenotype produced by this mutation causes cohesion defects, proliferation capacity reduction and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS. In summary, we provide the first evidence that loss of acetyltransferase activity contributes to the pathogenesis of RBS, underscoring the essential role of the enzymatic activity of the Eco1p family of proteins.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/hmg/ddn116
dc.identifier.issnISSN: 0964-6906
dc.identifier.issnEISSN: 1460-2083
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/27087
dc.language.isoengspa
dc.publisherOxford University Pressspa
dc.relation.citationEndPage2180
dc.relation.citationIssueNo. 14
dc.relation.citationStartPage2172
dc.relation.citationTitleHuman Molecular Genetics
dc.relation.citationVolumeVol. 17
dc.relation.ispartofHuman Molecular Genetics, ISSN: 0964-6906;EISSN: 1460-2083, Vol.17, No.14 (15 July 2008); pp. 2172–2180spa
dc.relation.urihttps://academic.oup.com/hmg/article/17/14/2172/926138spa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.sourceHuman Molecular Geneticsspa
dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subject.keywordPhenotypespa
dc.subject.keywordMutationspa
dc.subject.keywordCell cyclespa
dc.subject.keywordHypersensitivityspa
dc.subject.keywordGrowth retardationspa
dc.subject.keywordAcetyltransferasespa
dc.subject.keywordCell deathspa
dc.subject.keywordCell linesspa
dc.subject.keywordCentromerespa
dc.subject.keywordChromatidsspa
dc.subject.keywordCraniofacial abnormalitiesspa
dc.subject.keywordDnaspa
dc.subject.keywordFrameshift mutation functionspa
dc.subject.keywordMissense mutationspa
dc.subject.keywordRnaspa
dc.subject.keywordMessengeryspa
dc.subject.keywordChromosomesspa
dc.subject.keywordArmspa
dc.subject.keywordMitomycinspa
dc.subject.keywordMutationspa
dc.subject.keywordNonsensespa
dc.subject.keywordPhocomeliaspa
dc.subject.keywordRoberts-sc phocomelia syndromespa
dc.subject.keywordLongitudinal deficiency of limbspa
dc.titleThe molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activityspa
dc.title.TranslatedTitleEl mecanismo molecular subyacente al síndrome de Roberts implica la pérdida de la actividad acetiltransferasa de la ESCO2spa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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