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The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm

Robustness and completion of DNA replication rely on redundant DNA replication origins. Reduced efficiency of origin licensing is proposed to contribute to chromosome instability in CDK-deregulated cell cycles, a frequent alteration in oncogenesis. However, the mechanism by which this instability oc...

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Autores principales: Ayuda-Durán, Pilar, Devesa, Fernando, Gomes, Fábia, Sequeira-Mendes, Joana, Ávila-Zarza, Carmelo, Gómez, María, Calzada, Arturo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066753/
https://www.ncbi.nlm.nih.gov/pubmed/24753426
http://dx.doi.org/10.1093/nar/gku313
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author Ayuda-Durán, Pilar
Devesa, Fernando
Gomes, Fábia
Sequeira-Mendes, Joana
Ávila-Zarza, Carmelo
Gómez, María
Calzada, Arturo
author_facet Ayuda-Durán, Pilar
Devesa, Fernando
Gomes, Fábia
Sequeira-Mendes, Joana
Ávila-Zarza, Carmelo
Gómez, María
Calzada, Arturo
author_sort Ayuda-Durán, Pilar
collection PubMed
description Robustness and completion of DNA replication rely on redundant DNA replication origins. Reduced efficiency of origin licensing is proposed to contribute to chromosome instability in CDK-deregulated cell cycles, a frequent alteration in oncogenesis. However, the mechanism by which this instability occurs is largely unknown. Current models suggest that limited origin numbers would reduce fork density favouring chromosome rearrangements, but experimental support in CDK-deregulated cells is lacking. We have investigated the pattern of origin firing efficiency in budding yeast cells lacking the CDK regulators Cdh1 and Sic1. We show that each regulator is required for efficient origin activity, and that both cooperate non-redundantly. Notably, origins are differentially sensitive to CDK deregulation. Origin sensitivity is independent on normal origin efficiency, firing timing or chromosomal location. Interestingly, at a chromosome arm, there is a shortage of origin firing involving active and dormant origins, and the extent of shortage correlates with the severity of CDK deregulation and chromosome instability. We therefore propose that CDK deregulation in G1 phase compromises origin redundancy by decreasing the number of active and dormant origins, leading to origin shortage and increased chromosome instability.
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spelling pubmed-40667532014-06-24 The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm Ayuda-Durán, Pilar Devesa, Fernando Gomes, Fábia Sequeira-Mendes, Joana Ávila-Zarza, Carmelo Gómez, María Calzada, Arturo Nucleic Acids Res Genome Integrity, Repair and Replication Robustness and completion of DNA replication rely on redundant DNA replication origins. Reduced efficiency of origin licensing is proposed to contribute to chromosome instability in CDK-deregulated cell cycles, a frequent alteration in oncogenesis. However, the mechanism by which this instability occurs is largely unknown. Current models suggest that limited origin numbers would reduce fork density favouring chromosome rearrangements, but experimental support in CDK-deregulated cells is lacking. We have investigated the pattern of origin firing efficiency in budding yeast cells lacking the CDK regulators Cdh1 and Sic1. We show that each regulator is required for efficient origin activity, and that both cooperate non-redundantly. Notably, origins are differentially sensitive to CDK deregulation. Origin sensitivity is independent on normal origin efficiency, firing timing or chromosomal location. Interestingly, at a chromosome arm, there is a shortage of origin firing involving active and dormant origins, and the extent of shortage correlates with the severity of CDK deregulation and chromosome instability. We therefore propose that CDK deregulation in G1 phase compromises origin redundancy by decreasing the number of active and dormant origins, leading to origin shortage and increased chromosome instability. Oxford University Press 2014-07-01 2014-04-21 /pmc/articles/PMC4066753/ /pubmed/24753426 http://dx.doi.org/10.1093/nar/gku313 Text en © Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Ayuda-Durán, Pilar
Devesa, Fernando
Gomes, Fábia
Sequeira-Mendes, Joana
Ávila-Zarza, Carmelo
Gómez, María
Calzada, Arturo
The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm
title The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm
title_full The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm
title_fullStr The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm
title_full_unstemmed The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm
title_short The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm
title_sort cdk regulators cdh1 and sic1 promote efficient usage of dna replication origins to prevent chromosomal instability at a chromosome arm
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066753/
https://www.ncbi.nlm.nih.gov/pubmed/24753426
http://dx.doi.org/10.1093/nar/gku313
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