Somatic hypermutations are introduced into rearranged immunoglobulin variable (V) genes at a frequency of 10-2 mutations per base pair by an unknown mechanism. DNA repair pathways may generate or remove mutations, which predicts that the frequency and pattern of mutation will be different in V genes from mice defective in repair. Therefore, hypermutation was studied in mice deficient for mismatch and nucleotide excision repair. There were similar frequencies of mutation in rearranged Vκ Ox1 genes from immunized wildtype, PMS2-mismatch repair-deficient, and XPA-nucleotide excision repair-deficient mice. The pattern of mutation was also similar in V genes from XPA-deficient and wildtype mice, but was different in V genes from PMS2-deficient mice, which had a significant increase in the number of adjacent base substitutions. A biochemical assay was used to measure the efficiency of repair of tandem mismatches by various cell lines defective for DNA repair genes. Tandem mispairs were repaired by wildtype and Xpa-/- cells but not by Pms2-/- cells. The analysis of hypermutation in mice deficient for DNA repair has revealed two new findings. First, neither mismatch repair nor nucleotide excision repair are required to generate hypermutation in V genes. Second, tandem base substitutions were frequently found in V genes from Pms2-/- mice, suggesting that they are produced during the hypermutation process and then removed by a PMS2-dependent pathway. Biochemical evidence supports the existence of a novel pathway that processes tandem mispairs which requires PMS2.
|Original language||English (US)|
|State||Published - Mar 20 1998|
ASJC Scopus subject areas
- Molecular Biology