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

被引：127

作者：

Yeap, Leng-Siew ^{[1
,2
]}

Hwang, Joyce K. ^{[1
,2
]}

Du, Zhou ^{[1
,2
]}

Meyers, Robin M. ^{[1
,2
]}

Meng, Fei-Long ^{[1
,2
]}

Jakubauskaite, Agne ^{[1
,2
]}

Liu, Mengyuan ^{[1
,2
]}

Mani, Vinidhra ^{[1
,2
]}

Neuberg, Donna ^{[3
]}

Kepler, Thomas B. ^{[4
]}

Wang, Jing H. ^{[1
,2
]}

Alt, Frederick W. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Boston Childrens Hosp, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[4] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02215 USA

来源：

CELL | 2015年 / 163卷 / 05期

关键词：

CLASS SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; REGION; DELETIONS; TRANSCRIPTION; ACCUMULATION; INSERTIONS; HOTSPOTS;

D O I：

10.1016/j.cell.2015.10.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 hot-spots 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.

引用

页码：1124 / 1137

页数：14

共 45 条

[1] Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System [J].