title: Dual control of Yen1 nuclease activity and cellular localization by Cdk and Cdc14 prevents genome instability.
abstract: The careful orchestration of cellular events such as DNA replication, repair, and segregation is essential for equal distribution of the duplicated genome into two daughter cells. To ensure that persistent recombination intermediates are resolved prior to cell division, the Yen1 Holliday junction resolvase is activated at anaphase. Here, we show that the master cell-cycle regulators, cyclin-dependent kinase (Cdk) and Cdc14 phosphatase, control the actions of Yen1. During S phase, Cdk-mediated phosphorylation of Yen1 promotes its nuclear exclusion and inhibits catalytic activity by reducing the efficiency of DNA binding. Later in the cell cycle, at anaphase, Cdc14 drives Yen1 dephosphorylation, leading to its nuclear relocalization and enzymatic activation. Using a constitutively activated form of Yen1, we show that uncontrolled Yen1 activity is detrimental to the cell: spatial and temporal restriction of Yen1 protects against genotoxic stress and, by avoiding competition with the noncrossover-promoting repair pathways, prevents loss of heterozygosity.
authors.affiliation: London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Blanco
authors.affiliation: London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
authors.forename: Joao
authors.initials: J
authors.lastname: Matos
authors.affiliation: London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK. Electronic address: stephen.west@cancer.org.uk.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
mesh_terms: D021581:Active Transport, Cell Nucleus; D000705:Anaphase; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology*; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal; D042822:Genomic Instability; D045565:Holliday Junction Resolvases / Q000235:genetics / Q000378:metabolism*; D019656:Loss of Heterozygosity; D009154:Mutation; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C074860:CDC14 protein, S cerevisiae; D018797:Cell Cycle Proteins; D029701:Saccharomyces cerevisiae Proteins; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases; D045565:Holliday Junction Resolvases; C533749:Yen1 protein, S cerevisiae; D017027:Protein Tyrosine Phosphatases