PMS2-deficiency diminishes hypermutation of a lambda1 transgene in young but not older mice.
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.
Kong
Q
Q
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520-8114, USA.
Maizels
N
N
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
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