Normal somatic hypermutation of Ig genes in the absence of 8-hydroxyguanine-DNA glycosylase

J Immunol. 2003 Jun 1;170(11):5558-62. doi: 10.4049/jimmunol.170.11.5558.

Abstract

The hypermutation cascade in Ig V genes can be initiated by deamination of cytosine in DNA to uracil by activation-induced cytosine deaminase and its removal by uracil-DNA glycosylase. To determine whether damage to guanine also contributes to hypermutation, we examined the glycosylase that removes oxidized guanine from DNA, 8-hydroxyguanine-DNA glycosylase (OGG1). OGG1 has been reported to be overexpressed in human B cells from germinal centers, where mutation occurs, and could be involved in initiating Ab diversity by removing modified guanines. In this study, mice deficient in Ogg1 were immunized, and V genes from the H and kappa L chain loci were sequenced. Both the frequency of mutation and the spectra of nucleotide substitutions were similar in ogg1(-/-) and Ogg1(+/+) clones. More importantly, there was no significant increase in G:C to T:A transversions in the ogg1(-/-) clones, which would be expected if 8-hydroxyguanine remained in the DNA. Furthermore, Ogg1 was not up-regulated in murine B cells from germinal centers. These findings show that hypermutation is unaffected in the absence of Ogg1 activity and indicate that 8-hydroxyguanine lesions most likely do not cause V gene mutations.

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / enzymology
  • Base Composition
  • Clone Cells
  • DNA-Formamidopyrimidine Glycosylase
  • Gene Frequency / immunology
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Gene Rearrangement, B-Lymphocyte, Light Chain
  • Genes, Immunoglobulin / genetics*
  • Germinal Center / cytology
  • Germinal Center / enzymology
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / metabolism
  • Immunoglobulin Variable Region / genetics
  • Immunoglobulin Variable Region / metabolism
  • Immunoglobulin kappa-Chains / genetics
  • Immunoglobulin kappa-Chains / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Glycosyl Hydrolases / biosynthesis
  • N-Glycosyl Hydrolases / deficiency*
  • N-Glycosyl Hydrolases / genetics*
  • Somatic Hypermutation, Immunoglobulin*
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Immunoglobulin kappa-Chains
  • N-Glycosyl Hydrolases
  • DNA-Formamidopyrimidine Glycosylase