Journal
PLOS ONE
Volume 5, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0011182
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Funding
- Spanish Ministry of Education and Science [EX-2006-0732]
- LLS Fellowship
- Albert Einstein College of Medicine [T32 GM 007288]
- National Women's Division of the Albert Einstein College of Medicine
- [RO1CA76329]
- [RO1CA93484]
- [RO1CA72649]
- [RO1CA102705]
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Mismatch repair of AID-generated dU:G mispairs is critical for class switch recombination (CSR) and somatic hypermutation (SHM) in B cells. The generation of a previously unavailable Msh2(-/-) Msh6(-/-) mouse has for the first time allowed us to examine the impact of the complete loss of MutS alpha on lymphomagenesis, CSR and SHM. The onset of T cell lymphomas and the survival of Msh2(-/-) Msh6(-/-) and Msh2(-/-) Msh6(-/-) Msh3(-/-) mice are indistinguishable from Msh2(-/-) mice, suggesting that MSH2 plays the critical role in protecting T cells from malignant transformation, presumably because it is essential for the formation of stable MutS alpha heterodimers that maintain genomic stability. The similar defects on switching in Msh2(-/-), Msh2(-/-)Msh6(-/-) and Msh2(-/-)Msh6(-/-)Msh3(-/-) mice confirm that MutS alpha but not MutS beta plays an important role in CSR. Analysis of SHM in Msh2(-/-)Msh6(-/-) mice not only confirmed the error-prone role of MutS alpha in the generation of strand biased mutations at A:T bases, but also revealed an error-free role of MutS alpha when repairing some of the dU:G mispairs generated by AID on both DNA strands. We propose a model for the role of MutS alpha at the immunoglobulin locus where the local balance of error-free and error-prone repair has an impact in the spectrum of mutations introduced during Phase 2 of SHM.
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