A coming-of-age story: activation-induced cytidine deaminase turns 10 - PubMed (original) (raw)

Review

. 2009 Nov;10(11):1147-53.

doi: 10.1038/ni.1799. Epub 2009 Oct 20.

Affiliations

Review

A coming-of-age story: activation-induced cytidine deaminase turns 10

Rebecca K Delker et al. Nat Immunol. 2009 Nov.

Abstract

The discovery and characterization of activation-induced cytidine deaminase (AID) 10 years ago provided the basis for a mechanistic understanding of secondary antibody diversification and the subsequent generation and maintenance of cellular memory in B lymphocytes, which signified a major advance in the field of B cell immunology. Here we celebrate and review the triumphs in the mission to understand the mechanisms through which AID influences antibody diversification, as well as the implications of AID function on human physiology. We also take time to point out important ongoing controversies and outstanding questions in the field and highlight key experiments and techniques that hold the potential to elucidate the remaining mysteries surrounding this vital protein.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Antibody diversification. (a) A deletional recombination event between individual V, D and J segments creates the variable region of the immunoglobulin gene. This process is catalyzed by the RAG-1–RAG-2 recombinase complex and occurs in an antigen-independent way. C, constant. (b) SHM, the first of two secondary antibody-diversification processes, results in the accumulation of point mutations in the recombined variable region. AID initiates this process through the deamination of cytidine to uridine, followed by removal of the uracil base by UNG and repair by several base-excision repair (BER) and mismatch-repair (MMR) enzymes. The asterisk indicates the rearranged, mutated variable region. (c) CSR completes the secondary antibody diversification and results in the exchange of the default constant region, Cμ (IgM), for one of many downstream regions (Cγ3 (IgG3) is presented here). AID is thought to initiate this process through deamination of bases in the switch (S) region (yellow circles) upstream of each constant region, resulting in the formation of DSBs and recombination.

Figure 2

Figure 2

Specific localization to the nuclear periphery may be important for DSB repair. Left, persistent DSBs in S. cerevisiae are tethered to the nuclear pore complex (NPC) and are sequestered from the rest of the genome. This localization may require the integral inner nuclear membrane protein Mps3 and is dependent on the kinases Mec1 and Tel1 (ATM and ATR in humans). These interactions are thought to then shuttle the DSBs to a complex containing the pore protein Nup84 and the SUMO ligase Slx5-Slx8 (RNF4 in humans). In yeast, these interactions are thought to facilitate an alternative pathway of repair that enhances gene conversion through template-switch recombination. Right, evidence regarding the importance of the AID carboxy-terminal nuclear-export signal (NES) in CSR suggests that similar sequestration to the nuclear pore may occur and should be studied. It is possible that this is promoted by binding of a cofactor to AID or even by the formation of an RNA-containing complex. This model is completely speculative but emphasizes the importance of a foray into high-resolution microscopy to understand the nuclear localization of AID and the immunoglobulin locus. An understanding of both could provide insight into the mechanism of CSR and also provide an assay for the identification of other proteins or cellular factors necessary for CSR.

Similar articles

Cited by

References

    1. Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. CA Cancer J Clin. 1976;26:119–121. - PubMed
    1. Lederberg J. Genes and antibodies. Science. 1959;129:1649–1653. - PubMed
    1. Weigert MG, Cesari IM, Yonkovich SJ, Cohn M. Variability in the λ light chain sequences of mouse antibody. Nature. 1970;228:1045–1047. - PubMed
    1. Crews S, Griffin J, Huang H, Calame K, Hood L. A single VH gene segment encodes the immune response to phosphorylcholine: somatic mutation is correlated with the class of the antibody. Cell. 1981;25:59–66. - PubMed
    1. Selsing E, Storb U. Somatic mutation of immunoglobulin light-chain variable-region genes. Cell. 1981;25:47–58. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources