ALTERED SPECTRA OF HYPERMUTATION IN ANTIBODIES FROM MICE DEFICIENT FOR THE DNA MISMATCH REPAIR PROTEIN PMS2

Mutations are introduced into rearranged Ig variable genes at a freque ncy of 10(-2) mutations per base pair by an unknown mechanism. Assumin g that DNA repair pathways generate or remove mutations, the frequency and pattern of mutation will be different in variable genes from mice defective in repair. Therefore, hypermutation was studied in mice def icient for either the DNA nucleotide excision repair gene Xpa or the m ismatch repair gene Pms2. High levels of mutation were found in variab le genes from XPA-deficient and PMS2-deficient mice, indicating that n either nucleotide excision repair nor mismatch repair pathways generat e hypermutation. However, variable genes from PMS2-deficient mice had significantly more adjacent base substitutions than genes from wild-ty pe or XPA-deficient mice. By using a biochemical assay, we confirmed t hat tandem mispairs were repaired by wild-type cells but not by Pms2(- /-) human or murine cells. The data indicate that tandem substitutions are produced by the hypermutation mechanism and then processed by a P MS2-dependent pathway.