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Cell. 2015 Nov 19;163(5):1124-1137. doi: 10.1016/j.cell.2015.10.042. Epub 2015 Nov 12.

Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes.

Author information

1
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Microbiology, Boston University School of Medicine, Boston, MA 02215, USA.
4
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: alt@enders.tch.harvard.edu.

Abstract

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 the implications of these findings for harnessing antibody diversification mechanisms.

PMID:
26582132
PMCID:
PMC4751889
DOI:
10.1016/j.cell.2015.10.042
[Indexed for MEDLINE]
Free PMC Article

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