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PMID: 22231403 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2.

Nature structural & molecular biology ·Vol. 19 ·No. 2 ·2012-01-08 ·Pages 246-52

Buis J, Stoneham T, Spehalski E, Ferguson DO

Abstract

Homologous recombination facilitates accurate repair of DNA double-strand breaks (DSBs) during the S and G2 phases of the cell cycle by using intact sister chromatids as sequence templates. Homologous recombination capacity is maximized in S and G2 by cyclin-dependent kinase (CDK) phosphorylation of CtIP, which subsequently interacts with BRCA1 and the Mre11-Rad50-NBS1 (MRN) complex. Here we show that, in human and mouse, Mre11 controls these events through a direct interaction with CDK2 that is required for CtIP phosphorylation and BRCA1 interaction in normally dividing cells. CDK2 binds the C terminus of Mre11, which is absent in an inherited allele causing ataxia telangiectasia-like disorder. This newly uncovered role for Mre11 does not require ATM activation or nuclease activities. Therefore, functions of MRN are not restricted to DNA damage responses but include regulating homologous recombination capacity during the normal mammalian cell cycle.

MeSH Terms
Animals Carrier Proteins/metabolism Cell Cycle Proteins/metabolism Cyclin-Dependent Kinase 2/metabolism DNA Breaks, Double-Stranded DNA Repair DNA Repair Enzymes/metabolism DNA-Binding Proteins/metabolism Endodeoxyribonucleases Humans MRE11 Homologue Protein Mice Mice, Knockout Nuclear Proteins/metabolism Phosphorylation Protein Binding Protein Interaction Mapping Recombination, Genetic
Chemicals
Carrier Proteins Cell Cycle Proteins CtIP protein, mouse DNA-Binding Proteins MRE11 protein, human Mre11a protein, mouse Nuclear Proteins CDK2 protein, human Cdk2 protein, mouse Cyclin-Dependent Kinase 2 Endodeoxyribonucleases MRE11 Homologue Protein RBBP8 protein, human DNA Repair Enzymes
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Buis Jeffrey
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
Stoneham Trina
Spehalski Elizabeth
Ferguson David O
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.2212
Published
2012-01-08
Epub
2012-00-08
Pages
246-52
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC3272152
Subset
IM
Grants
NCI NIH HHS · 5-P30-CA46592 · United States
NHLBI NIH HHS · R01 HL079118-05S1 · United States
NIAID NIH HHS · T32 AI007413-12 · United States
NIGMS NIH HHS · F32 GM087073-01A1 · United States
NIGMS NIH HHS · F32-GM087073 · United States
NHLBI NIH HHS · R01 HL079118-06 · United States
NHLBI NIH HHS · R01 HL079118 · United States
NCI NIH HHS · T32 CA009676 · United States
NIGMS NIH HHS · F32 GM087073-02 · United States
NIAID NIH HHS · T32 AI007413 · United States
NIAID NIH HHS · T32-AI007413 · United States
NCI NIH HHS · P30 CA046592 · United States
NHLBI NIH HHS · R01-HL079118 · United States
NHLBI NIH HHS · R01 HL079118-07 · United States
External Links
PubMed source DOI: 10.1038/nsmb.2212 PMC Full Text View journal details
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