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Cell. 2015 Aug 13;162(4):751-65. doi: 10.1016/j.cell.2015.07.009. Epub 2015 Jul 30.

RAG Represents a Widespread Threat to the Lymphocyte Genome.

Author information

1
Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA.
2
Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
3
Division of Biomedical Informatics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Box 9066, Dallas, TX 75390-9066, USA.
4
Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.
5
Department of Immunology and Microbiology, College of Medicine, Xi'an Jiao Tong University, 76 Yan Ta West Road, Box 37, Xian, Shaanxi 710061, PRC.
6
Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: casellar@mail.nih.gov.
7
Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA; Howard Hughes Medical Institute, 295 Congress Avenue, New Haven, CT 06511, USA. Electronic address: david.schatz@yale.edu.

Abstract

The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis-targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes. The mouse and human genomes appear to have responded by reducing the abundance of "cryptic" recombination signals near RAG1 binding sites. This depletion operates specifically on the RSS heptamer, whereas nonamers are enriched at RAG1 binding sites. Reversing this RAG-driven depletion of cleavage sites by insertion of strong recombination signals creates an ectopic hub of RAG-mediated V(D)J recombination and chromosomal translocations. Our findings delineate rules governing RAG binding in the genome, identify areas at risk of RAG-mediated damage, and highlight the evolutionary struggle to accommodate programmed DNA damage in developing lymphocytes.

PMID:
26234156
PMCID:
PMC4537821
DOI:
10.1016/j.cell.2015.07.009
[Indexed for MEDLINE]
Free PMC Article

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