AID-initiated DNA lesions are differentially processed in distinct B cell populations (IRM8P.701)

Abstract

Abstract Activation-induced deaminase (AID) initiates U:G mismatches, causing point mutations or DNA double-stranded breaks at immunoglobulin (Ig) loci. How AID-initiated lesions are prevented from inducing genome-wide damage is not completely understood. Prior studies proposed a differential DNA repair mechanism that protects certain non-Ig loci such as c-myc from AID attack. However, determinants that regulate such protective mechanisms remain largely unknown. To test whether target DNA sequences might modulate protective mechanisms via modifying the processing manner of AID-initiated lesions, we established a knock-in model by inserting an Sγ2b region, a bona fide AID target, into the first intron of c-myc. Unexpectedly, we found that the inserted S region did not mutate or enhance genomic instability of c-myc, due to error-free repair of AID-initiated lesions, in antigen-stimulated germinal center B cells. In contrast, cytokine-activated B cells display a much higher level of c-myc genomic instability in an AID- and S region-dependent manner. Our findings reveal a complex interplay between target sequence, DNA repair mechanism, and cellular context associated with differential transcription, which coordinately regulate genome stability. Our studies could provide mechanistic insight into differential routes to AID-mediated genetic alterations in distinct subtypes of common B cell lymphomas.