The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081326
The Journal of Experimental Medicine, Vol. 206, No. 3, 669-679
The Rockefeller University Press, 0022-1007 $30.00
© Helmink et al.
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ARTICLE

 MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks

Beth A. Helmink1, Andrea L. Bredemeyer1, Baeck-Seung Lee1, Ching-Yu Huang1, Girdhar G. Sharma2, Laura M. Walker1, Jeffrey J. Bednarski1, Wan-Ling Lee1, Tej K. Pandita2, Craig H. Bassing3,4, and Barry P. Sleckman1

1 Department of Pathology and Immunology and 2 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110
3 Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
4 Abramson Family Cancer Research Institute, Philadelphia, PA 19104

CORRESPONDENCE Barry P. Sleckman: Sleckman{at}immunology.wustl.edu

The Mre11–Rad50–Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of antigen receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during lymphocyte antigen receptor gene assembly.

B.A. Helmink and A.L. Bredemeyer contributed equally to this paper.

Abbreviations used: ATM, ataxia telangiectasia mutated; DP, double positive; DSB, double-strand break; HR, homologous recombination; MRN, Mre11–Rad50–Nbs1; NHEJ, nonhomologous end joining; RS, recombination signal.

© 2009 Helmink et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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