Controlling somatic hypermutation in immunoglobulin variable and switch regions.
Activation-induced deaminase (AID) is a B-cell-specific enzyme required for initiating the mechanisms of affinity maturation and isotype switching of antibodies. AID functions by deaminating cytosine to uracil in DNA, which initiates a cascade of events resulting in mutations and strand breaks in the immunoglobulin loci. There is an intricate interplay between faithful DNA repair and mutagenic DNA repair during somatic hypermutation, in that some proteins from accurate repair pathways are also involved in mutagenesis. One factor that shifts the balance from faithful to mutagenic repair is the genomic sequence of the switch regions. Indeed, the sequence of the switch mu region is designed to maximize AID access to increase the abundance of clustered dU bases. The frequency and proximity of these dU nucleotides then in turn inhibit faithful repair and promote strand breaks.
Maul
Robert W
RW
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Gearhart
Patricia J
PJ
D000818:Animals; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D006801:Humans; D017578:Immunoglobulin Class Switching; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics; D051379:Mice; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007135:Immunoglobulin Variable Region; D007136:Immunoglobulins; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase