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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell 2015 ; 163 (5): 1124-37 Nephropedia Template TP
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Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes #MMPMID26582132
Yeap LS; Hwang JK; Du Z; Meyers RM; Meng FL; Jakubauskait? A; Liu M; Mani V; Neuberg D; Kepler TB; Wang JH; Alt FW
Cell 2015[Nov]; 163 (5): 1124-37 PMID26582132show ga
In activated B lymphocytes, AID initiates antibody variable (V) exon somatic hypermutation (SHM) for affinity maturation in germinal centers (GCs) and IgH switch (S) region DNA breaks (DSBs) for class-switch recombination (CSR). To resolve long-standing questions, we have developed an in vivo assay to study AID-targeting of passenger sequences replacing a V exon. First, we find AID targets SHM hotspots within V exon and S region passengers at similar frequencies and that the normal SHM process frequently generates deletions, indicating that SHM and CSR employ the same mechanism. Second, AID mutates targets in diverse non-Ig passengers in GC B cells at levels similar to those of V exons, definitively establishing the V exon location as "privileged" for SHM. Finally, Peyer's patch GC B cells generate a reservoir of V exons that are highly mutated before selection for affinity maturation. We discuss implications of these findings for harnessing antibody diversification mechanisms.