title: The Cdk/cDc14 module controls activation of the Yen1 holliday junction resolvase to promote genome stability.
abstract: Faithful genome transmission during cell division requires precise, coordinated action of DNA metabolic enzymes, including proteins responsible for DNA damage detection and repair. Dynamic phosphorylation plays an important role in controlling repair enzymes during the DNA damage response (DDR). Cdc14 phosphatases oppose cyclin-dependent kinase (Cdk) phosphorylation and have been implicated in the DDR in several model systems. Here, we have refined the substrate specificity of budding yeast Cdc14 and, using this insight, identified the Holliday junction resolvase Yen1 as a DNA repair target of Cdc14. Cdc14 activation at anaphase triggers nuclear accumulation and enzymatic activation of Yen1, likely to resolve persistent recombinational repair intermediates. Consistent with this, expression of a phosphomimetic Yen1 mutant increased sister chromatid nondisjunction. In contrast, lack of Cdk phosphorylation resulted in constitutive activity and elevated crossover-associated repair. The precise timing of Yen1 activation, governed by core cell-cycle regulators, helps coordinate DNA repair with chromosome segregation and safeguards against genome destabilization.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Christie L
authors.initials: CL
authors.lastname: Eissler
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Mazón
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Brendan L
authors.initials: BL
authors.lastname: Powers
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Savinov
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Lorraine S
authors.initials: LS
authors.lastname: Symington
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: mchall@purdue.edu.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hall
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation; D015825:Chromosomes, Fungal; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; 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*; D008938:Mitosis; D009154:Mutation; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013997:Time Factors
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