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Review
. 2005 Jun:1050:146-62.
doi: 10.1196/annals.1313.119.

DNA lesions and repair in immunoglobulin class switch recombination and somatic hypermutation

Zhenming Xu  1 , Zsolt Fulop, Yuan Zhong, Albert J Evinger 3rd, Hong Zan, Paolo Casali
Affiliations
Review

DNA lesions and repair in immunoglobulin class switch recombination and somatic hypermutation

Zhenming Xu et al. Ann N Y Acad Sci. 2005 Jun.

Abstract

Immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) are critical for the maturation of the antibody response. These processes endow antibodies with increased antigen-binding affinity and acquisition of new biological effector functions, thereby underlying the generation of memory B cells and plasma cells. They are dependent on the generation of specific DNA lesions and the intervention of activation-induced cytidine deaminase as well as newly identified translesion DNA polymerases, which are expressed in germinal center B cells. DNA lesions include mismatches, abasic sites, nicks, single-strand breaks, and double-strand breaks (DSBs). DSBs in the switch (S) region DNA are critical for CSR, but they also occur in V(D)J regions and possibly contribute to the events that lead to SHM. The nature of the DSBs in the Ig locus, their generation, and the repair processes that they trigger and that are responsible for their regulation remain poorly understood. Aberrant regulation of these events can result in chromosomal breaks and translocations, which are significant steps in B-cell neoplastic transformation.

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Figures

FIGURE 1
FIGURE 1
RAG and AID in B-cell differentiation. V(D)J recombination times B-cell development. It occurs in bone marrow and is dependent on the expression of RAG1 and RAG2, but not AID. Eventually, IgM+ B cells will leave the bone marrow and colonize the peripheral lymphoid organs. They will be activated by encounter with antigen and undergo SHM and CSR. Both processes are dependent on AID expression, but not RAG1/RAG2. SHM inserts mainly point mutations in the variable region, whereas CSR changes the constant region of the IgH chain with a downstream CH region, thereby “looping-out” the intervening DNA.
FIGURE 2
FIGURE 2
Phylogenetic emergence of SHM and CSR and development of adaptive immunity. From jawed fish to humans, SHM first emerges in cold-blooded vertebrates. CSR emerges first in amphibians. Both SHM and CSR are fully operational in mammals.
FIGURE 3
FIGURE 3
Generation of DSBs in S regions. (a) AID-dependent generation of DSBs: deamination of cytosine on both strands generates U:G mismatches, which will activate either the mismatch repair pathway (MMR) or the base excision pathway (BER). The MMR complex, consisting of Msh2, Msh6, Mlh1, Pms2, and Exo1, would generate gaps in opposite DNA strands and eventually DSBs. In the BER pathway, uracil DNA glycosylase (UDG) removes the uracil base to yield an abasic site, which in turn is cleaved off by apyrimidinic endonuclease to generate nicks and, when cleaving on opposite strands, DSBs. (b) AID-independent generation of DSBs and their processing by AID. DNA strands are cleaved to form blunt-ended DSBs by a yet to be defined endonuclease. AID-dependent processing of the blunt ends leads to the U:G mismatches, which eventually yield resected DSBs. In either a or b, whether upstream or downstream of blunt-ended DSBs, AID would be critical in generating resected free DNA ends.
FIGURE 4
FIGURE 4
Protein factors bound to DNA DSBs. (a) The S-wt and S-mt oligonucleo-tide sequences. (b) The gel picture from an electrical mobility shift assay during which the 32P-radiolabeled S-wt or S-mt was incubated without (lanes 1 and 2) or with (lanes 3 and 4) total CL-01 cell lysates on ice for 30 minutes. The DNA-protein complexes were separated through a 5% PAGE and then subjected to autoradiography. Arrowheads indicate three proteins or protein complexes specifically bound to the S-wt, but not S-mt; *Two proteins/protein complexes that are bound to both S-wt and S-mt. (c) Model depicting different proteins/ protein complexes involved in DSB repair during CSR. Processing of blunt-end DSBs by AID and its cofactors yields resected ends. A putative end-protecting factor prevents re-ligation of the ends intra-S regions until they are replaced by a recombinase complex while the intergenic region “loops out”. The recombinase either fills in or further resects the ends to undergo an NHEJ process. Alternatively, the resected ends are repaired by HR.
FIGURE 5
FIGURE 5
DSBs and error-prone repair in SHM. Blunt-ended DSBs generated in a rearranged IgH variable region would recruit Mre11, Rad50, and Nbs1 as well as phosphorylated H2AX. They would be repaired by NHEJ through Ku70/Ku80 and DNA ligase. Alternatively, they would undergo AID processing to yield 3′ protruding ends, which recruit Rad51/Rad52 to initiate HR through invasion of sister chromatids or homologous chromosomes. A chromatin remodeling protein or a DNA helicase is likely involved in making the homologous region accessible. Different translesion DNA polymerases, upregulated in germinal center B cells, participate in the error-prone repairing process. Pol ι inserts incorrect single nucleotides, while polymerase ζ extends the DNA strand past the insertion. Pol θ could both insert mismatched nucleotides and extend the terminus. However, the mismatched terminus generated by pol θ could also be extended by pol ζ.
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