Article abstract
Nature Structural & Molecular Biology 16, 808 - 813 (2009)
Published online: 26 July 2009 | doi:10.1038/nsmb.1639
Multiple functions of MRN in end-joining pathways during isotype class switching
Maria Dinkelmann1,3, Elizabeth Spehalski1,3, Trina Stoneham1, Jeffrey Buis1, Yipin Wu1, JoAnn M Sekiguchi2 & David O Ferguson1
Abstract
The Mre11–Rad50–NBS1 (MRN) complex has many roles in response to DNA double-strand breaks, but its functions in repair by nonhomologous end joining (NHEJ) pathways are poorly understood. We have investigated requirements for MRN in class switch recombination (CSR), a programmed DNA rearrangement in B lymphocytes that requires NHEJ. To this end, we have engineered mice that lack the entire MRN complex in B lymphocytes or that possess an intact complex that harbors mutant Mre11 lacking DNA nuclease activities. MRN deficiency confers a strong defect in CSR, affecting both the classic and the alternative NHEJ pathways. In contrast, absence of Mre11 nuclease activities causes a milder phenotype, revealing a separation of function within the complex. We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the classical and alternative NHEJ pathways.
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
- Departments of Internal Medicine and Human Genetics, The University of Michigan, Ann Arbor, Michigan, USA.
- These authors contributed equally to this work.
Correspondence to: David O Ferguson1 e-mail: daviferg@umich.edu
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