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, 5 (11), 1101-3

Class Switching and Myc Translocation: How Does DNA Break?

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Class Switching and Myc Translocation: How Does DNA Break?

Paolo Casali et al. Nat Immunol.

Abstract

Chromosomal translocations involving immunoglobulin switch regions are commonly thought to arise from aberrant AID-induced DNA lesions. New data, however, suggest AID does not initiate such lesions, but acts subsequently in the B cell transformation process.

Figures

Figure 1
Figure 1
Generation of DSBs in S regions. (a) DNA deamination: AID directly deaminates cytidine residues in DNA, converting them to uridine residues. The G:U mismatch can then be processed by either the base-excision repair (BER) pathway (the major pathway) or by the mismatch-repair (MMR) machinery, which includes mutS homolog 1 (Msh1), Msh6, mutL homologue 1 (Mlh1) and postmitotic segregation (Pms), to introduce gaps or nicks on opposite strands of the S-region DNA. The nicks induced by the base-excision repair pathway are thought to be generated by the following process: UNG removes the AID-introduced deoxyuridine, thereby creating an abasic site that is processed by APE1 to yield a DNA nick. (b) RNA deamination and editing: AID deaminates mRNA through recognition by specific cofactors, and mRNA thus edited is translated into a putative endonuclease, which cleaves DNA to generate DSB. (c) The work by Unniraman et al. together with the findings by Begum et al. cast considerable doubt on the models summarized in a and b and lend strong support to the idea of AID-independent generation of DSB: Blunt DSBs are generated in yet-to-be-determined way independently of AID. In the absence of AID, these DSB ends are ligated intra-S region through nonhomologous end-joining. After stimulation by activated CD4+ T cells, AID is upregulated and recruited to DSB, perhaps through a cofactor, to deaminate cytidine near the free DNA ends and generate U:G mismatches. UDG mediated attack on the mispaired U would lead to the generation of an abasic site, which becomes the substrate of APE1 to yield DNA nicks and give rise to resected DNA ends (U:G mispairs could also be processed through the BER or MMR pathways, as shown in a). A second possibility is that AID, together with specific cofactors, deaminates and edits mRNA, specifying an endonuclease that resects DNA ends. Finally, a third possibility is that AID, together with specific cofactors, deaminates and edits mRNA that is translated into a recombinase, which remodels chromatin in a way that facilitates S-region synapsis and inter-S-S-region recombination.

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