Model for MMR resolution of AID-generated dU:G mispairs.
In the DNA deamination model, MSH2/MSH6 recognizes the initial AID-generated dU:G lesion, the damaged strand is excised by Exo1, and Polη is preferentially recruited to the nontranscribed strand (NTS) to generate mutations at A sites within WA motifs. Fewer T sites within TW motifs are mutated, contributing to the singular A≫T and WA≫TW biases that characterize SHM and reflect the reduced targeting of A sites by Polη in the transcribed strand (TS). We highlight here the error-free repair effect of MMR at the dU:G mispairs within the excised patch, which is revealed in Msh2−/−Msh6−/− mice by a significant increase in unrepaired dU:G lesions that are replicated as transitions at C:G sites in WRC/GYW hotspots (i.e. C-to-T within WRC in the NTS, and G-to-A within GYW as a reflection of C-to-T mutations in the TS).