Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice

Curr Biol. 2002 Oct 15;12(20):1748-55. doi: 10.1016/s0960-9822(02)01215-0.

Abstract

Background: We have previously proposed that deamination of cytosine to uracil at sites within the immunoglobulin loci by activation-induced deaminase (AID) triggers antibody diversification. The pattern of diversification (phase 1 or 2 hypermutation, gene conversion, or switch recombination) is viewed as depending on the mode of resolution of the dU/dG lesion. A major resolution mode involves excising the uracil, an activity that at least four different enzymes can accomplish in the mouse.

Results: Deficiency in UNG uracil-DNA glycosylase alone is sufficient to distort the pathway of hypermutation in mice. In ung(-/-) animals, mutations at dC/dG pairs are dramatically shifted toward transitions (95%), indicating that the generation of abasic sites (which can induce transversions) has been inhibited. The pattern of substitutions at dA/dT pairs is unaffected. Class-switch recombination is substantially, but not totally, inhibited.

Conclusions: The results provide strong support for the DNA deamination model for antibody diversification with respect to class-switching as well as hypermutation and, in the context of this model, suggest that (i) UNG is the major mouse DNA glycosylase responsible for processing the programmed dU/dG lesions within the immunoglobulin locus; (ii) the second (dA/dT-biased) phase of mutation is probably triggered by recognition of the initiating dU/dG lesion; and (iii) switch recombination largely proceeds via formation of an abasic site, although (iv) an UNG-independent pathway of switch recombination exists, which could reflect action by another uracil-DNA glycosylase but might alternatively be explained by a distinct pathway of resolution, for example, one involving MSH2/MSH6 recognition of the dU/dG lesion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Diversity
  • DNA Glycosylases*
  • Immunoglobulin Class Switching / drug effects
  • Immunoglobulin Class Switching / genetics
  • Immunoglobulin Class Switching / immunology*
  • Immunoglobulin G / blood
  • Immunoglobulin Isotypes / blood
  • Interleukin-4 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Knockout
  • Mutagenesis
  • N-Glycosyl Hydrolases / deficiency*
  • N-Glycosyl Hydrolases / genetics
  • N-Glycosyl Hydrolases / metabolism*
  • Somatic Hypermutation, Immunoglobulin / genetics*
  • Uracil-DNA Glycosidase

Substances

  • Immunoglobulin G
  • Immunoglobulin Isotypes
  • Lipopolysaccharides
  • Interleukin-4
  • DNA Glycosylases
  • N-Glycosyl Hydrolases
  • Uracil-DNA Glycosidase