Msh2 ATPase activity is essential for somatic hypermutation at a-T basepairs and for efficient class switch recombination.
Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase-mediated cytidine deamination of immunoglobulin genes. MutS homologue (Msh) 2-/- mice have reduced A-T mutations and CSR. This suggests that Msh2 may play a role in repairing activation-induced cytidine deaminase-generated G-U mismatches. However, because Msh2 not only initiates mismatch repair but also has other functions, such as signaling for apoptosis, it is not known which activity of Msh2 is responsible for the effects observed, and consequently, many models have been proposed. To further dissect the role of Msh2 in SHM and CSR, mice with a "knockin" mutation in the Msh2 gene that inactivates the adenosine triphosphatase domain were examined. This mutation (i.e., Msh2G674A), which does not affect apoptosis signaling, allows mismatches to be recognized but prevents Msh2 from initiating mismatch repair. Here, we show that, similar to Msh2-/- mice, SHM in Msh2G674A mice is biased toward G-C mutations. However, CSR is partially reduced, and switch junctions are more similar to those of postmeiotic segregation 2-/- mice than to Msh2-/- mice. These results indicate that Msh2 adenosine triphosphatase activity is required for A-T mutations, and suggest that Msh2 has more than one role in CSR.
Martin
Alberto
A
Department of Immunology, University of Toronto, Medical Sciences Bldg., Toronto, Canada, M5S 1A8. alberto.martin@utoronto.ca
Li
Ziqiang
Z
Lin
Diana P
DP
Bardwell
Philip D
PD
Iglesias-Ussel
Maria D
MD
Edelmann
Winfried
W
Scharff
Matthew D
MD
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D020029:Base Pairing; D004260:DNA Repair; D004268:DNA-Binding Proteins; D017578:Immunoglobulin Class Switching; D007134:Immunoglobulin Switch Region; D051379:Mice; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein