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

Somatic Hypermutation Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2012; 188(11):5528-37. DOI: 10.4049/jimmunol.1102629
Source: PubMed


To test the hypothesis that DNA polymerase ζ participates in Ig hypermutation, we generated two mouse models of Pol ζ function: a B cell-specific conditional knockout and a knock-in strain with a Pol ζ mutagenesis-enhancing mutation. Pol ζ-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 ζ 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 ζ. Combined, these data are best explained by a direct role for DNA polymerase ζ in Ig hypermutation.

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    • "In yeast, there is additional evidence that MNMs are created by the activity of DNA polymerase zeta (Pol z), an error-prone translesion polymerase that extends DNA synthesis past mismatches and damage-induced lesions (Sakamoto et al. 2007; Stone et al. 2012). Pol z is also responsible for MNMs that occur during somatic hypermutation of the variable regions of mouse immunoglobulins (Daly et al. 2012; Saribasak et al. 2012). These results were established by knocking out Pol z in mutant yeast strains and adult mouse cells, but it has not been possible to knock out Pol z in Ó 2014 Harris and Nielsen This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see "
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