title: Cdk1 restrains NHEJ through phosphorylation of XRCC4-like factor Xlf1.
abstract: Eukaryotic cells use two principal mechanisms for repairing DNA double-strand breaks (DSBs): homologous recombination (HR) and nonhomologous end-joining (NHEJ). DSB repair pathway choice is strongly regulated during the cell cycle. Cyclin-dependent kinase 1 (Cdk1) activates HR by phosphorylation of key recombination factors. However, a mechanism for regulating the NHEJ pathway has not been established. Here, we report that Xlf1, a fission yeast XLF ortholog, is a key regulator of NHEJ activity in the cell cycle. We show that Cdk1 phosphorylates residues in the C terminus of Xlf1 over the course of the cell cycle. Mutation of these residues leads to the loss of Cdk1 phosphorylation, resulting in elevated levels of NHEJ repair in vivo. Together, these data establish that Xlf1 phosphorylation by Cdc2(Cdk1) provides a molecular mechanism for downregulation of NHEJ in fission yeast and indicates that XLF is a key regulator of end-joining processes in eukaryotic organisms.
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hentges
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Waller
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras 2781-901, Portugal.
authors.forename: Clara C
authors.initials: CC
authors.lastname: Reis
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras 2781-901, Portugal.
authors.forename: Miguel Godinho
authors.initials: MG
authors.lastname: Ferreira
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK. Electronic address: ajd21@sussex.ac.uk.
authors.forename: Aidan J
authors.initials: AJ
authors.lastname: Doherty
mesh_terms: D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D059766:DNA End-Joining Repair; D015536:Down-Regulation; D059765:Homologous Recombination; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029702:Schizosaccharomyces pombe Proteins; C519230:XLF1 protein, S pombe; D016203:CDC2 Protein Kinase