CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination

TY - JOUR

T1 - CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination

AU - Falck, Jacob

AU - Forment, Josep V

AU - Coates, Julia

AU - Mistrik, Martin

AU - Lukas, Jiri

AU - Bartek, Jiri

AU - Jackson, Stephen P

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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.

KW - Amino Acid Substitution

KW - CDC2 Protein Kinase

KW - Cell Cycle Proteins

KW - Cell Line, Tumor

KW - DNA Breaks, Double-Stranded

KW - DNA Cleavage

KW - DNA Repair

KW - DNA Repair Enzymes

KW - DNA Replication

KW - DNA-Binding Proteins

KW - Homologous Recombination

KW - Humans

KW - Mutagenesis, Site-Directed

KW - Nuclear Proteins

KW - Phosphorylation

KW - Protein Processing, Post-Translational

KW - Serine

U2 - 10.1038/embor.2012.58

DO - 10.1038/embor.2012.58

M3 - Journal article

C2 - 22565321

SN - 1469-221X

VL - 13

SP - 561

EP - 568

JO - E M B O Reports

JF - E M B O Reports

IS - 6

ER -