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Normal Somatic Hypermutation of Ig Genes in the Absence of 8-Hydroxyguanine-DNA Glycosylase

David B. Winter^1,*, Quy H. Phung^*, Xianmin Zeng^*, Erling Seeberg, Deborah E. Barnes, Tomas Lindahl and Patricia J. Gearhart^2,*

^* Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Molecular Biology, Institute of Medical Microbiology, University of Oslo, The National Hospital, Oslo, Norway; Clare Hall Laboratories, Cancer Research UK, London Research Institute, London, United Kingdom

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 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.