DNA double-strand breaks: prior to but not sufficient in targeting hypermutation.
The activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin (Ig) genes, both of which are associated with DNA double-strand breaks (DSBs). As AID is capable of deaminating deoxy-cytidine (dC) to deoxy-uracil (dU), it might induce nicks (single strand DNA breaks) and also DNA DSBs via a U-DNA glycosylase-mediated base excision repair pathway ('DNA-substrate model'). Alternatively, AID functions like its closest homologue Apobec1 as a catalytic subunit of a RNA editing holoenzyme ('RNA-substrate model'). Although rearranged Vlambda genes are preferred targets of SHM we found that germinal center (GC) B cells of AID-proficient and -deficient Vlambda1-expressing GC B cells display a similar frequency, distribution, and sequence preference of DSBs in rearranged and also in germline Vlambda1 genes. The possible roles of DSBs in relation to AID function and SHM are discussed.
Bross
Linda
L
Basel Institute for Immunology, CH-4005 Basel, Switzerland.
Muramatsu
Masamichi
M
Kinoshita
Kazuo
K
Honjo
Tasuku
T
Jacobs
Heinz
H
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D003564:Cytidine Deaminase / Q000378:metabolism; D043525:Cytosine Deaminase; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004249:DNA Damage; D017931:DNA Primers; D003841:Deoxycytidine / Q000378:metabolism; D005803:Genes, Immunoglobulin; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000378:metabolism; D007438:Introns; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009700:Nucleoside Deaminases / Q000235:genetics; D017393:RNA Editing; D013154:Spleen / Q000201:enzymology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D017931:DNA Primers; D007145:Immunoglobulin kappa-Chains; D003841:Deoxycytidine; D004247:DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D003564:Cytidine Deaminase