Abstract
Secondary diversification of the antibody repertoire upon antigenic challenge, in the form of immunoglobulin heavy chain (IgH) class-switch recombination (CSR) endows mature, naïve B cells in peripheral lymphoid organs with a limitless ability to mount an optimal humoral immune response, thus expediting pathogen elimination. CSR replaces the default constant (CH) region exons (Cμ) of IgH with any of the downstream CH exons (Cγ, Cε, or Cα), thereby altering effector functions of the antibody molecule. This process depends on, and is orchestrated by, activation-induced deaminase (AID), a DNA cytidine deaminase that acts on single-stranded DNA exposed during transcription of switch (S) region sequences at the IgH locus. DNA lesions thus generated are processed by components of several general DNA repair pathways to drive CSR. Given that AID can instigate DNA lesions and genomic instability, stringent checks are imposed that constrain and restrict its mutagenic potential. In this review, we will discuss how AID expression and substrate specificity and activity is rigorously enforced at the transcriptional, post-transcriptional, post-translational, and epigenetic levels, and how the DNA-damage response is choreographed with precision to permit targeted activity while limiting bystander catastrophe.
Highlights
B cells are specialized lymphocytes that express Ig receptors on their cell surface
In the context of specialized structures called germinal centers in secondary lymphoid organs such as the spleen and lymph nodes, mature B cells interact with antigens and undergo class-switch recombination (CSR) [2, 3]
This finding is in contrast to proposed distributive mode of action based on the high net positive charge (+11 at pH 7.0) of activation-induced deaminase (AID) that promotes strong binding to nucleic acids [15]
Summary
B cells are specialized lymphocytes that express Ig receptors (or antibodies) on their cell surface. A salient feature of B-lymphocytes is their ability to recognize an almost infinite array of antigens This enormous diversity is achieved through V(D)J recombination, a process that assembles the exons encoding the amino-terminal variable regions of IgH and IgL from component variable (V), diversity (D), and joining (J) segments [1]. Germinal center B cells undergo another AID-dependent secondary diversification reaction termed somatic hypermutation (SHM) wherein point mutations, and sometimes insertions and deletions, are introduced at a very high rate (10−2– 10−3/bp/generation) into the recombined variable region exons encoding IgH and IgL, so as to select B cells with increased antigen affinity (Figure 1). INTRINSIC PROPERTIES OF AID Following the discovery of AID by subtractive cDNA hybridization from the mouse CH12F3 B lymphoma cells and its proven essentiality for SHM and CSR [8, 9], a huge amount of effort has www.frontiersin.org
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