Reevaluation of the role of DNA polymerase θ in somatic hypermutation of immunoglobulin genes

DNA polymerase θ has been implicated in the process of somatic hypermutation in immunoglobulin variable genes based on several reports of alterations in the frequency and spectra of mutations from Polq^-/- mice. However, these studies have contrasting results on mutation frequencies and the types of nucleotide substitutions, which question the role of polymerase θ in hypermutation. DNA polymerase η has a dominant effect on mutation and may substitute in the absence of polymerase θ to affect the pattern. Therefore, we have examined mutation in mice deficient for both polymerases θ and η. The mutation frequencies in rearranged variable genes from Peyer's patches were similar in wild type, Polq^-/-, Polh^-/-, and Polq^-/-Polh^-/- mice. The types of substitutions were also similar between wild type and Polq^-/- clones, and between Polh^-/- and Polq^-/-Polh^-/- clones. Furthermore, there was no difference in heavy chain class switching in splenic B cells from the four groups of mice. These results indicate that polymerase θ does not play a significant role in the generation of somatic mutation in immunoglobulin genes.