Article abstract
Nature Structural & Molecular Biology 16, 819 - 824 (2009)
Published online: 26 July 2009 | doi:10.1038/nsmb.1641
Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells
Emilie Rass1,3, Anastazja Grabarz1,3, Isabelle Plo1, Jean Gautier2, Pascale Bertrand1 & Bernard S Lopez1
Abstract
Here we have used an intrachromosomal substrate to monitor the end joining of distant ends, which leads to DNA rearrangements in mammalian cells. We show that silencing Mre11 reduces the efficiency of nonhomologous end joining (NHEJ), affecting both the canonical and alternative pathways, partly in a manner that is independent of the ataxia-telangiectasia mutated kinase (ATM). Silencing of Rad50 or CtIP decreases end-joining efficiency in the same pathway as Mre11. In cells defective for Xrcc4, the MRE11–RAD50–NBS1 (MRN) complex inhibitor MIRIN decreases end-joining frequencies, demonstrating a role for MRN in alternative NHEJ. Consistently, MIRIN sensitizes both complemented and NHEJ-defective cells to ionizing radiation. Conversely, overexpression of Mre11 stimulates the resection of single-stranded DNA and increases alternative end joining, through a mechanism that requires Mre11's nuclease activity, but in an ATM-independent manner. These data demonstrate that, in addition to its role in ATM activation, Mre11 can favor alternative NHEJ through its nuclease activity.
- Unité mixte de recherche 217, Centre National de la Recherche Scientifique-Commissariat à l'Energie Atomique, Equipe labellisée LA LIGUE 2008, Institut de Radiobiologie Cellulaire et Moléculaire, Fontenay-aux-Roses, France.
- Department of Genetics and Development, Columbia University, New York, New York, USA.
- These authors contributed equally to this study.
Correspondence to: Pascale Bertrand1 e-mail: pascale.bertrand@cea.fr
Correspondence to: Bernard S Lopez1 e-mail: bernard.lopez@cea.fr
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