CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination
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CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination. / Falck, Jacob; Forment, Josep V; Coates, Julia; Mistrik, Martin; Lukas, Jiri; Bartek, Jiri; Jackson, Stephen P.
In: E M B O Reports, Vol. 13, No. 6, 06.2012, p. 561-8.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 13
SP - 561
EP - 568
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 6
ER -
ID: 110601451