Role of Mre11 in Chromosomal Nonhomologous End Joining in Mammalian Cells

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2009 Jul 28

PMID 19633668

Citations 200

Authors

Emilie Rass

Anastazja Grabarz

Isabelle Plo

Jean Gautier

Pascale Bertrand

Bernard S Lopez

Affiliations

Soon will be listed here.

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.

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