title: The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm.
abstract: 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.
authors.affiliation: Department of Microbial Biotechnology, Centro Nacional de Biotecnología CNB-CSIC, Darwin 3, Madrid 28049, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ayuda-Durán
authors.affiliation: Department of Microbial Biotechnology, Centro Nacional de Biotecnología CNB-CSIC, Darwin 3, Madrid 28049, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Devesa
authors.affiliation: Department of Microbial Biotechnology, Centro Nacional de Biotecnología CNB-CSIC, Darwin 3, Madrid 28049, Spain.
authors.forename: Fábia
authors.initials: F
authors.lastname: Gomes
authors.affiliation: Centro de Biología Molecular Severo Ochoa CBMSO-CSIC/UAM, Nicolás Cabrera 1, Madrid 28049, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Sequeira-Mendes
authors.affiliation: Department of Statistics, Universidad de Salamanca, Salamanca 37007, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Avila-Zarza
authors.affiliation: Centro de Biología Molecular Severo Ochoa CBMSO-CSIC/UAM, Nicolás Cabrera 1, Madrid 28049, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez
authors.affiliation: Department of Microbial Biotechnology, Centro Nacional de Biotecnología CNB-CSIC, Darwin 3, Madrid 28049, Spain arturo.calzada@csic.es.
authors.forename: Arturo
authors.initials: A
authors.lastname: Calzada
mesh_terms: D064200:Cdh1 Proteins / Q000235:genetics / Q000502:physiology*; D043171:Chromosomal Instability; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D042522:DNA Replication Timing; D017353:Gene Deletion; D018628:Gene Dosage; D018741:Replication Origin; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C577583:CDH1 protein, S cerevisiae; D064200:Cdh1 Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins
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