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Absence of the spindle assembly checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion

2018-09Journal article Open access
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dc.contributor.authorSilva, Rui
dc.contributor.authorMirkovic, Mihailo
dc.contributor.authorGuilgur, Leonardo G.
dc.contributor.authorRathore, Om
dc.contributor.authorMartinho, Rui Goncalo
dc.contributor.authorOliveira, Raquel A.
dc.date.accessioned2018-12-07T14:58:10Z
dc.date.available2018-12-07T14:58:10Z
dc.date.issued2018-09
dc.description.abstractThe fidelity of mitosis depends on cohesive forces that keep sister chromatids together. This is mediated by cohesin that embraces sister chromatid fibers from the time of their replication until the subsequent mitosis [1-3]. Cleavage of cohesin marks anaphase onset, where single chromatids are dragged to the poles by the mitotic spindle [4-6]. Cohesin cleavage should only occur when all chromosomes are properly bio-oriented to ensure equal genome distribution and prevent random chromosome segregation. Unscheduled loss of sister chromatid cohesion is prevented by a safeguard mechanism known as the spindle assembly checkpoint (SAC) [7, 8]. To identify specific conditions capable of restoring defects associated with cohesion loss, we screened for genes whose depletion modulates Drosophila wing development when sister chromatid cohesion is impaired. Cohesion deficiency was induced by knockdown of the acetyltransferase separation anxiety (San)/Naa50, a cohesin complex stabilizer [9-12]. Several genes whose function impacts wing development upon cohesion loss were identified. Surprisingly, knockdown of key SAC proteins, Mad2 and Mpsl, suppressed developmental defects associated with San depletion. SAC impairment upon cohesin removal, triggered by San depletion or artificial removal of the cohesin complex, prevented extensive genome shuffling, reduced segregation defects, and restored cell survival. This counterintuitive phenotypic suppression was caused by an intrinsic bias for efficient chromosome biorientation at mitotic entry, coupled with slow engagement of error-correction reactions. Thus, in contrast to SAC's role as a safeguard mechanism for mitotic fidelity, removal of this checkpoint alleviates mitotic errors when sister chromatid cohesion is compromised.
dc.description.sponsorshipLisboa Regional Operational Programme (Lisboa 2020) through the European Regional Development Fund (FEDER); Fundacao para a Ciencia e a Tecnologia (FCT; Portugal); FCT [SFRH/BPD/87482/2012, SFRH /BD/52438/2013, PD/BD/52428/2013, PD/00117/2012, CRM: 0027030, PTDC/BEX-BID/0395/2014, UID/BIM/04773/2013 CBMR 1334, IF/00851/2012/CP0185/CT0004]; Association for International Cancer Research [AICR 10-0553]; EMBO Installation Grant [IG2778]; European Research Council Starting Grant [ERC-2014-STG-638917]; [PPBI-POCI-01-0145-FEDER-022122]; [LISBOA-01-0145-FEDER-022170]
dc.identifier.doi10.1016/j.cub.2018.06.062
dc.identifier.issn0960-9822
dc.identifier.issn1879-0445
dc.identifier.urihttp://hdl.handle.net/10400.1/11896
dc.language.isoeng
dc.peerreviewedyes
dc.publisherCell Press
dc.relationChromosome Architecture and the Fidelity of Mitosis during Development
dc.subjectSaccharomyces-Cerevisiae
dc.subjectTopoisomerase-Ii
dc.subjectSeparation
dc.subjectDrosophila
dc.subjectChromosomes
dc.subjectCleavage
dc.subjectMitosis
dc.subjectCentromeres
dc.subjectAnaphase
dc.subjectCells
dc.titleAbsence of the spindle assembly checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleChromosome Architecture and the Fidelity of Mitosis during Development
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/638917/EU
oaire.citation.endPage+
oaire.citation.issue17
oaire.citation.startPage2837
oaire.citation.titleCurrent Biology
oaire.citation.volume28
oaire.fundingStreamH2020
person.familyNameSilva
person.familyNameRathore
person.familyNameViegas Russo da Conceição Martinho
person.givenNameRui
person.givenNameOm
person.givenNameRui Gonçalo
person.identifier.ciencia-idF31D-C783-3D89
person.identifier.orcid0000-0003-2168-8599
person.identifier.orcid0000-0003-3858-557X
person.identifier.orcid0000-0002-1641-3403
person.identifier.ridC-5622-2012
person.identifier.ridM-7546-2013
person.identifier.scopus-author-id15045741700
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublicationfca82a46-5e9b-4371-8e9c-cdec0dde45c7
relation.isAuthorOfPublication8891c3b2-0f45-4db4-8772-b1dadcf89585
relation.isAuthorOfPublication.latestForDiscovery8891c3b2-0f45-4db4-8772-b1dadcf89585
relation.isProjectOfPublication1f76dc07-1c5b-42ad-8822-5ec827aae626
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