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

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 κ 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.

Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells

“…An S phasespecific increase in NEIL1 expression suggests an involvement in replicationassociated repair of oxidized bases (61). None of these recently identified enzymes would appear to correspond to a hypothetical DNA glycosylase activity that might excise modified G residues opposite deaminated cytosine to account for the A:T phase of somatic hypermutation in immunoglobulin genes; OGG1 is not involved in this process (153).…”

B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis

“…SHM may be triggered, and possibly be also maintained in germinal center B cells, by immune complexes formed by IgG antibodies bound to the antigen [15,19,28,29]. It is particularly not clear how the processes of SHM and selection interact dynamically and temporally to shape the memory B-cell repertoire, on which the system depends for fast antigen elimination in subsequent encounters [30][31][32][33], although several models have been suggested based on imaging studies [34][35][36]. Bioinformatical approaches utilized so far in the study of affinity maturation include the analysis of the frequencies of specific types of mutation [37][38][39][40][41][42][43][44][45] and mathematical models exploring the dynamical interactions between SHM and clonal selection [46][47][48][49][50][51] and their spatial segregation [52][53][54][55].…”

Expression of human 8-oxoguanine DNA glycosylase (hOGG1) in follicular lymphoma

“…It is unlikely, however, that downregulation of hOGG1 by itself leads to the formation of follicular lymphoma since a recent study shows that somatic hypermutation of immunoglobulin genes, a key function of germinal center B cells, remain intact in the absence of hOGG1 gene expression in knockout mice. 1 Also, these knockout mice do not have an increased rate of developing malignancy. 1,17 Additionally, although the number of cases is relatively small in this study, hOGG1 expression in follicular lymphoma did not correlate with disease stage at presentation, overall survival, or response to therapy (data not shown).…”

“…1 Also, these knockout mice do not have an increased rate of developing malignancy. 1,17 Additionally, although the number of cases is relatively small in this study, hOGG1 expression in follicular lymphoma did not correlate with disease stage at presentation, overall survival, or response to therapy (data not shown). Taken together, our findings suggest that downregulation of hOGG1 expression may be an early event in lymphomagenesis.…”