New origin firing is inhibited by APC/CCdh1 activation in S-phase after severe replication stress
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- dc.contributor.author Ercilla, Amaiaca
- dc.contributor.author Llopis, Albaca
- dc.contributor.author Feu, Soniaca
- dc.contributor.author Aranda Aragón, Sergioca
- dc.contributor.author Ernfors, Patrikca
- dc.contributor.author Freire, Raimundoca
- dc.contributor.author Agell, Neusca
- dc.date.accessioned 2017-01-25T07:42:39Z
- dc.date.available 2017-01-25T07:42:39Z
- dc.date.issued 2016ca
- dc.description.abstract Defects in DNA replication and repair are known to promote genomic instability, a hallmark of cancer cells. Thus, eukaryotic cells have developed complex mechanisms to ensure accurate duplication of their genomes. While DNA damage response has been extensively studied in tumour cells, the pathways implicated in the response to replication stress are less well understood especially in non-transformed cells. Here we show that in non-transformed cells, APC/CCdh1 is activated upon severe replication stress. Activation of APC/CCdh1 prevents new origin firing and induces permanent arrest in S-phase. Moreover, Rad51-mediated homologous recombination is also impaired under these conditions. APC/CCdh1 activation in S-phase occurs after replication forks have been processed into double strand breaks. Remarkably, this activation, which correlates with decreased Emi1 levels, is not prevented by ATR/ATM inhibition, but it is abrogated in cells depleted of p53 or p21. Importantly, we found that the lack of APC/CCdh1 activity correlated with an increase in genomic instability. Taken together, our results define a new APC/CCdh1 function that prevents cell cycle resumption after prolonged replication stress by inhibiting origin firing, which may act as an additional mechanism in safeguarding genome integrity.
- dc.description.sponsorship This work was supported by Ministerio de Economia y Competitividad [SAF2013–42742-R to N.A., SAF2013-49149-R to R.F.]; Red Temática de investigación cooperativa en cáncer [RD 12/0036/0049 to N.A.]; FPI-fellowship from Ministerio de ciencia e innovación (to A.E. and A.L.); FI-fellowship from Generalitat de Catalunya (to S.F.)
- dc.format.mimetype application/pdfca
- dc.identifier.citation Ercilla A, Llopis A, Feu S, Aranda Aragón S, Ernfors P, Freire R, Agell N. New origin firing is inhibited by APC/CCdh1 activation in S-phase after severe replication stress. Nucleic Acids Research. 2016; 44(10): 4745-4762. DOI: 10.1093/nar/gkw132ca
- dc.identifier.doi http://dx.doi.org/10.1093/nar/gkw132
- dc.identifier.issn 0305-1048ca
- dc.identifier.uri http://hdl.handle.net/10230/27978
- dc.language.iso engca
- dc.publisher Oxford University Pressca
- dc.relation.ispartof Nucleic Acids Research. 2016; 44(10): 4745-4762
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013–42742-R
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49149-R
- dc.rights © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
- dc.subject.keyword Cell cycle
- dc.subject.keyword DNA
- dc.subject.keyword DNA damage
- dc.subject.keyword DNA replication
- dc.subject.keyword S phase
- dc.subject.keyword Stress
- dc.subject.keyword E-cadherin
- dc.title New origin firing is inhibited by APC/CCdh1 activation in S-phase after severe replication stressca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca