J Exp Med. 2016 Jul 25. pii: jem.20151227.
DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes.
National Institute on Aging, National Institutes of Health, Baltimore, MD 21224. State University of New York, Stony Brook, NY 11794. National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20850. University of Texas MD Anderson Cancer Center Science Park, Smithville, TX 78957.
Service type: Knock-in mice
DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-in mice that express full-length Pol ι that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ι did not change overall mutagenesis. We next examined if Pol ι affected tandem mutations generated by another error-prone polymerase, Pol ζ. 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 ι-compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol ι occasionally accesses the replication fork to generate a first mutation, and Pol ζ extends the mismatch with a second mutation.View Publication