The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1).
G(1) cell cycle regulators are often mutated in cancer, but how this causes genomic instability is unclear. Here we show that yeast lacking the CDK inhibitor Sic1 initiate DNA replication from fewer origins, have an extended S phase, and inefficiently separate sister chromatids during anaphase. This leads to double-strand breaks (DSBs) in a fraction of sic1 cells as evidenced by the accumulation of Ddc1 foci and a 575-fold increase in gross chromosomal rearrangements. Both S and M phase defects are rescued by delaying S-CDK activation, indicating that Sic1 promotes origin licensing in late G(1) by preventing the untimely activation of CDKs. We propose that precocious CDK activation causes genomic instability by altering the dynamics of S phase, which then hinders normal chromosome segregation.
Lengronne
Armelle
A
Institute of Molecular Genetics, CNRS UMR 5535 and Université Montpellier II, France.
Schwob
Etienne
E
D018797:Cell Cycle Proteins / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D004249:DNA Damage; D004261:DNA Replication; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000502:physiology*; D016193:G1 Phase / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D018741:Replication Origin / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D015003:Yeasts / Q000235:genetics*
D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C440013:Ddc1 protein, S cerevisiae; D005656:Fungal Proteins; D010750:Phosphoproteins; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins