Normal somatic hypermutation of Ig genes in the absence of 8-hydroxyguanine-DNA glycosylase.
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.
Winter
David B
DB
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Phung
Quy H
QH
Zeng
Xianmin
X
Seeberg
Erling
E
Barnes
Deborah E
DE
Lindahl
Tomas
T
Gearhart
Patricia J
PJ
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology; D001482:Base Composition; D002999:Clone Cells; D043382:DNA-Formamidopyrimidine Glycosylase; D005787:Gene Frequency / Q000276:immunology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D005803:Genes, Immunoglobulin / Q000235:genetics*; D018858:Germinal Center / Q000166:cytology / Q000201:enzymology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009699:N-Glycosyl Hydrolases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase