MSH2/MSH6 complex promotes error-free repair of AID-Induced dU: G mispairs as well as error-prone hypermutation of A:T Sites

Sergio Roa, Ziqiang Li, Jonathan U. Peled, Chunfang Zhao, Winfried Edelmann, Matthew D. Scharff

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 MutSα 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 MutSα heterodimers that maintain genomic stability. The similar defects on switching in Msh2-/-, Msh2-/-Msh6-/- and Msh2-/-Msh6-/-Msh3-/- mice confirm that MutSα but not MutSβ plays an important role in CSR. Analysis of SHM in Msh2-/-Msh6-/- mice not only confirmed the error-prone role of MutSα in the generation of strand biased mutations at A:T bases, but also revealed an error-free role of MutSα when repairing some of the dU:G mispairs generated by AID on both DNA strands. We propose a model for the role of MutSα 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.

Original languageEnglish (US)
Article numbere11182
JournalPLoS One
Volume5
Issue number6
DOIs
StatePublished - 2010

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Repair
T-cells
Switches
mice
Genetic Recombination
T-lymphocytes
mutation
Mutation
DNA Mismatch Repair
T-Cell Lymphoma
Genomic Instability
Immunoglobulins
lymphoma
immunoglobulins
Cells
B-lymphocytes
Cell Survival
B-Lymphocytes
Defects
DNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

MSH2/MSH6 complex promotes error-free repair of AID-Induced dU : G mispairs as well as error-prone hypermutation of A:T Sites. / Roa, Sergio; Li, Ziqiang; Peled, Jonathan U.; Zhao, Chunfang; Edelmann, Winfried; Scharff, Matthew D.

In: PLoS One, Vol. 5, No. 6, e11182, 2010.

Research output: Contribution to journalArticle

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