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Mismatch repair co-opted by hypermutation

M Cascalho1, J Wong, C Steinberg

  • 1Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0670, USA.

Science (New York, N.Y.)
|March 21, 1998
PubMed
Summary

The mismatch repair gene Pms2 normally fixes DNA errors. In this study, Pms2 deficiency surprisingly increased mutations, suggesting mismatch repair aids somatic hypermutation in B cells.

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Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • The mismatch repair (MMR) system corrects DNA replication errors.
  • Mice with disrupted MMR genes, like Pms2, typically exhibit a mutator phenotype.
  • Somatic hypermutation (SHM) introduces diversity in immunoglobulin genes during B cell development.

Purpose of the Study:

  • To investigate the role of the Pms2 mismatch repair gene in somatic hypermutation.
  • To determine if Pms2 deficiency affects mutation rates at immunoglobulin loci.
  • To elucidate the mechanism by which mismatch repair influences SHM in B cells.

Main Methods:

  • Generation of mice with a disrupted Pms2 allele crossed into a quasi-monoclonal (QM) mouse background.
  • Analysis of somatic mutation frequencies at immunoglobulin heavy chain and lambda chain loci.
  • Comparison of mutation rates between Pms2 homozygous knockout, heterozygous, and wild-type QM mice.

Main Results:

  • Mice homozygous for the disrupted Pms2 allele exhibited fewer somatic mutations at immunoglobulin loci compared to heterozygotes and wild-type QM mice.
  • This finding contradicts the expected mutator phenotype in the context of SHM.
  • Mismatch repair appears to promote, rather than inhibit, somatic hypermutation at these loci.

Conclusions:

  • The Pms2 mismatch repair gene plays a role in somatic hypermutation, potentially by fixing rather than eliminating mutations.
  • In hypermutable B cells, mismatch repair may direct the correction of mismatched base pairs towards the newly synthesized strand, thereby fixing mutations.
  • This suggests a novel mechanism where DNA repair pathways can contribute to genetic diversification in the immune system.

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