title: Cdk1-dependent regulation of the Mre11 complex couples DNA repair pathways to cell cycle progression.
abstract: Homologous recombination (HR) and non-homologous end joining (NHEJ) are the main pathways ensuring the repair of DNA double-stranded breaks (DSBs) in eukaryotes. It has long been known that cell cycle stage is a major determinant of the type of pathway used to repair DSBs in vivo. However, the mechanistic basis for the cell cycle regulation of the DNA damage response is still unclear. Here we show that a major DSB sensor, the Mre11-Rad50-Xrs2 (MRX) complex, is regulated by cell cycle-dependent phosphorylation specifically in mitosis. This modification depends on the cyclin-dependent kinase Cdc28/Cdk1, and abrogation of Xrs2 and Mre11 phosphorylation results in a marked preference for DSB repair through NHEJ. Importantly, we show that phosphorylation of the MRX complex after DNA damage and during mitosis are regulated independently of each other by Tel1/ATM and Cdc28/Cdk1 kinases. Collectively, our results unravel an intricate network of phosphoregulatory mechanisms that act through the MRX complex to modulate DSB repair efficiency during mitosis.
authors.affiliation: Institute for Research in Immunology and Cancer and Département de Pathologie et Biologie Cellulaire; Université de Montréal; Montréal, Québec, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Simoneau
authors.affiliation: Institute for Research in Immunology and Cancer and Département de Pathologie et Biologie Cellulaire; Université de Montréal; Montréal, Québec, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Robellet
authors.affiliation: Institute for Research in Immunology and Cancer and Département de Pathologie et Biologie Cellulaire; Université de Montréal; Montréal, Québec, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ladouceur
authors.affiliation: Institute for Research in Immunology and Cancer and Département de Pathologie et Biologie Cellulaire; Université de Montréal; Montréal, Québec, Canada.
authors.forename: Damien
authors.initials: D
authors.lastname: D'Amours
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004271:DNA, Fungal / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000378:metabolism*; D008938:Mitosis; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004271:DNA, Fungal; D029701:Saccharomyces cerevisiae Proteins; C086929:XRS2 protein, S cerevisiae; D016203:CDC2 Protein Kinase; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae
keywords: DNA repair; Mre11; Xrs2; cyclin-dependent kinase; mitosis