期刊
CELL
卷 163, 期 4, 页码 947-959出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.10.016
关键词
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资金
- NIH [AI020047, AI032524]
- LLS SCOR [7009-12]
- Robertson Foundation/Cancer Research Institute Irvington Fellowship
- Leukemia and Lymphoma Society
- NIH NRSA [AI007512]
RAG initiates antibody V(D)J recombination in developing lymphocytes by generating on-target'' DNA breaks at matched pairs of bona fide recombination signal sequences (RSSs). We employ bait RAG-generated breaks in endogenous or ectopically inserted RSS pairs to identify huge numbers of RAG off-target'' breaks. Such breaks occur at the simple CAC motif that defines the RSS cleavage site and are largely confined within convergent CTCF-binding element (CBE)-flanked loop domains containing bait RSS pairs. Marked orientation dependence of RAG off-target activity within loops spanning up to 2 megabases implies involvement of linear tracking. In this regard, major RAG off-targets in chromosomal translocations occur as convergent RSS pairs at enhancers within a loop. Finally, deletion of a CBE-based IgH locus element disrupts V(D) J recombination domains and, correspondingly, alters RAG on-and off-target distributions within IgH. Our findings reveal how RAG activity is developmentally focused and implicate mechanisms by which chromatin domains harness biological processes within them.
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