title: PMS2-deficiency diminishes hypermutation of a lambda1 transgene in young but not older mice.
abstract: The Pms2 gene is involved in DNA mismatch repair in mammalian cells, and has recently been shown to affect hypermutation of mammalian immunoglobulin genes. We have studied hypermutation of a lambda1 transgene in chronically stimulated Peyer's patch B cells of both young and old mice deficient in function of Pms2. In young (3-4 months) mice, somatic hypermutation is fourfold lower in PMS2-deficient mice than in control mice. This difference is statistically significant (P < 0.05). In contrast, in older mice (9 months of age), hypermutation levels are indistinguishable in the Pms2-/- and Pms2+/+ backgrounds. In the older mice, there was no clear difference in the fraction of clones carrying either any mutations or at least two mutations when PMS2-deficient mice were compared with their wild-type littermates. As genomic instability increases with age, this observation is difficult to reconcile with the hypothesis that highly mutated B cells cannot survive in Peyer's patches. Moreover, there were clear differences apparent in the mutation spectra of the Pms2-/- and Pms2+/+ mice. In the PMS2-deficient background, deletion and insertion mutations were found, and there was a significant decrease in the ratio of A mutations to T mutations in comparison with the Pms2+/+ controls. Our data support the hypothesis that PMS2 functions in somatic hypermutation, and are most consistent with the hypothesis that the role of PMS2 is direct rather than indirect.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520-8114, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Kong
authors.forename: N
authors.initials: N
authors.lastname: Maizels
mesh_terms: D000251:Adenosine Triphosphatases; D000375:Aging / Q000235:genetics*; D000818:Animals; D020137:Base Pair Mismatch; D001483:Base Sequence; D002213:Capsid / Q000235:genetics; D036022:Capsid Proteins; D003001:Cloning, Molecular; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D018014:Gene Transfer Techniques; D051379:Mice; D008822:Mice, Transgenic; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D036022:Capsid Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C090196:lambda 1 protein, reovirus; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes