INCREASED HYPERMUTATION AT G-NUCLEOTIDE AND C-NUCLEOTIDE IN IMMUNOGLOBULIN VARIABLE GENES FROM MICE DEFICIENT IN THE MSH2 MISMATCH REPAIR PROTEIN

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generat ed by an error-prone DNA polymerase, and the mismatch repair pathway m ay process the mispairs. To examine the role of the MSH2 mismatch repa ir protein in hypermutation, Msh2(-/-) mice were immunized with oxazol one, and B cells were analyzed for mutation in their V(k)Oxl light cha in genes. The frequency of mutation in the repair-deficient mice was s imilar to that in Msh2(+/+) mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bi as for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G a nd C.