Cell
Volume 162, Issue 4, 13 August 2015, Pages 751-765
Journal home page for Cell

Article
RAG Represents a Widespread Threat to the Lymphocyte Genome

https://doi.org/10.1016/j.cell.2015.07.009Get rights and content
Under an Elsevier user license
open archive

Highlights

  • The RAG endonuclease binds to thousands of sites in the lymphocyte genome

  • Off-target RAG activity is rare outside of the antigen receptor genes

  • Substrates for RAG cleavage are preferentially depleted at sites of RAG binding

  • RSSs inserted in the genome create a recombination and translocation hot spot

Summary

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.

Cited by (0)