Abstract
Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity.
Highlights
Mammalian adaptive immune responses require B cells to produce immunoglobulins (Igs), commonly known as antibodies, that can recognize a seemingly infinite number of antigens on foreign pathogens
This review describes the general mechanisms of class switch recombination (CSR) and highlights recent data on the localization of activation-induced cytidine deaminase (AID) to S regions and the DNA repair pathways that resolve AID-generated dU:dG lesions
Conditional deletion of two methyltransferases (Suv4-20h1 and Suv4-20h2), which are responsible for histone H4 lysine 20 di- and tri-methylation (H4K20me[2] and H4K20me3), in B cells leads to a 50% reduction in CSR53
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Any comments on the article can be found at the end of the article
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