title: CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination.
abstract: The conserved MRE11–RAD50–NBS1 (MRN) complex is an important sensor of DNA double-strand breaks (DSBs) and facilitates DNA repair by homologous recombination (HR) and end joining. Here, we identify NBS1 as a target of cyclin-dependent kinase (CDK) phosphorylation. We show that NBS1 serine 432 phosphorylation occurs in the S, G2 and M phases of the cell cycle and requires CDK activity. This modification stimulates MRN-dependent conversion of DSBs into structures that are substrates for repair by HR. Impairment of NBS1 phosphorylation not only negatively affects DSB repair by HR, but also prevents resumption of DNA replication after replication-fork stalling. Thus, CDK-mediated NBS1 phosphorylation defines a molecular switch that controls the choice of repair mode for DSBs.
authors.affiliation: Department of Biochemistry, Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
authors.forename: Jacob
authors.initials: J
authors.lastname: Falck
authors.forename: Josep V
authors.initials: JV
authors.lastname: Forment
authors.forename: Julia
authors.initials: J
authors.lastname: Coates
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrik
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D017766:Acid Anhydride Hydrolases; D019943:Amino Acid Substitution; D016203:CDC2 Protein Kinase / Q000737:chemistry / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D053837:DNA Cleavage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000737:chemistry; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry; D059765:Homologous Recombination; D006801:Humans; D000076228:MRE11 Homologue Protein; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D012694:Serine; D016203:CDC2 Protein Kinase; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes