TY - JOUR
T1 - Normal somatic hypermutation of Ig genes in the absence of 8-hydroxyguanine-DNA glycosylase
AU - Winter, David B.
AU - Phung, Quy H.
AU - Zeng, Xianmin
AU - Seeberg, Erling
AU - Barnes, Deborah E.
AU - Lindahl, Tomas
AU - Gearhart, Patricia J.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.170.11.5558
DO - 10.4049/jimmunol.170.11.5558
M3 - Article
C2 - 12759433
AN - SCOPUS:0038189578
SN - 0022-1767
VL - 170
SP - 5558
EP - 5562
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -