DNA polymerase ? functions in the generation of tandem mutations during somatic hypermutation of antibody genes.

ABSTRACT: DNA polymerase ? (Pol ?) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ?, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ?, and knock-in mice that express full-length Pol ? that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ? did not change overall mutagenesis. We next examined if Pol ? affected tandem mutations generated by another error-prone polymerase, Pol ?. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol ?-compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol ? occasionally accesses the replication fork to generate a first mutation, and Pol ? extends the mismatch with a second mutation.

SUBMITTER: Maul RW 

PROVIDER: S-EPMC4995076 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature