Generation and repair of AID-initiated DNA lesions in B lymphocytes

Abstract

Activation-induced deaminase (AID) initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation (SHM) and class switch recombination (CSR), both of which require AID. AID induces U:G mismatch lesions in DNA that are subsequently converted into point mutations or DNA double stranded breaks during SHM/CSR. In a physiological context, AID targets immunoglobulin (Ig) loci to mediate SHM/CSR. However, recent studies reveal genome-wide access of AID to numerous non-Ig loci. Thus, AID poses a threat to the genome of B cells if AID-initiated DNA lesions cannot be properly repaired. In this review, we focus on the molecular mechanisms that regulate the specificity of AID targeting and the repair pathways responsible for processing AID-initiated DNA lesions.

Figure 1

SHM and CSR at the Igh locus. The genomic configuration of rearranged mouse Igh locus is shown. AID introduces point mutations into variable (V) region exon during SHM. During CSR, AID induces DNA double strand breaks (DSBs) to donor Sμ and a downstream acceptor S region, with Sγ1 as an example. Broken S regions are rejoined via NHEJ pathway while intervening DNA is excised as a circle. Transcription is required for both SHM/CSR with promoters delineated for both V and S regions. Upon CSR, originally expressed Cμ exons are replaced by Cγ1 exons so that naïve IgM⁺ B cells switch to antigen experienced IgG1⁺ B cells. Vertical arrows: point mutations.

Figure 2

Processing of AID-initiated DNA lesions. AID deaminates C residue and converts it into Uracil (U). AID-initiated U:G mismatch can be processed via several different pathways. (1) General replication machinery can interpret U as T and pair it with A during subsequent replication. This pathway leads to typical C→T or G→A transition mutations at C:G base pair. (2) U:G mismatches can be recognized by UNG, together with error-prone repair, leading to transition or transversion mutations at C:G base pair. (3) MMR recognition of U:G mismatches and error-prone repair result in mutations at A:T base pair. (4) After MMR or UNG recognition, error-free repair can also correct the U:G mismatch lesions and result in the absence of mutations.