Altered Ig Hypermutation Pattern and Frequency in Complementary Mouse Models of DNA Polymerase ζ Activity

To test the hypothesis that DNA polymerase zeta participates in Ig hypermutation, we generated two mouse models of Pol zeta function: a B cell-specific conditional knockout and a knock-in strain with a Pol zeta mutagenesis-enhancing mutation. Pol zeta-deficient B cells had a reduction in mutation frequency at Ig loci in the spleen and in Peyer's patches, whereas knock-in mice with a mutagenic Pol zeta displayed a marked increase in mutation frequency in Peyer's patches, revealing a pattern that was similar to mutations in yeast strains with a homologous mutation in the gene encoding the catalytic subunit of Pol zeta. Combined, these data are best explained by a direct role for DNA polymerase zeta in Ig hypermutation. The Journal of Immunology, 2012, 188: 5528-5537.