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Molecular and Cellular Biology, May 2008, p. 3058-3069, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.02025-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Glycine-Arginine Domain in Control of the Human MRE11 DNA Repair Protein{triangledown} ,{dagger}

Ugo Déry,1 Yan Coulombe,1 Amélie Rodrigue,1 Andrzej Stasiak,2 Stéphane Richard,3 and Jean-Yves Masson1*

Genome Stability Laboratory, Laval University Cancer Research Center, Hotel-Dieu de Quebec, 9 McMahon, Quebec City G1R 2J6, Canada,1 Laboratory of Ultrastructural Analysis, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland,2 Terry Fox Molecular Oncology Group, Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research and Departments of Oncology and Medicine, McGill University, Montréal, Quebec, Canada3

Received 9 November 2007/ Returned for modification 13 December 2007/ Accepted 9 February 2008

Human MRE11 is a key enzyme in DNA double-strand break repair and genome stability. Human MRE11 bears a glycine-arginine-rich (GAR) motif that is conserved among multicellular eukaryotic species. We investigated how this motif influences MRE11 function. Human MRE11 alone or a complex of MRE11, RAD50, and NBS1 (MRN) was methylated in insect cells, suggesting that this modification is conserved during evolution. We demonstrate that PRMT1 interacts with MRE11 but not with the MRN complex, suggesting that MRE11 arginine methylation occurs prior to the binding of NBS1 and RAD50. Moreover, the first six methylated arginines are essential for the regulation of MRE11 DNA binding and nuclease activity. The inhibition of arginine methylation leads to a reduction in MRE11 and RAD51 focus formation on a unique double-strand break in vivo. Furthermore, the MRE11-methylated GAR domain is sufficient for its targeting to DNA damage foci and colocalization with {gamma}-H2AX. These studies highlight an important role for the GAR domain in regulating MRE11 function at the biochemical and cellular levels during DNA double-strand break repair.

* Corresponding author. Mailing address: Genome Stability Laboratory, Laval University Cancer Research Center, Hotel-Dieu de Quebec, 9 McMahon, Quebec City G1R 2J6, Canada. Phone: (418) 525-4444, ext. 15154. Fax: (418) 691-5439. E-mail: Jean-Yves.Masson{at}crhdq.ulaval.ca

{triangledown} Published ahead of print on 19 February 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2008, p. 3058-3069, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.02025-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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