RAG Represents a Widespread Threat to the Lymphocyte Genome

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Base Sequence
  • Binding Sites
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Genomic Instability*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Lymphocytes / cytology
  • Lymphocytes / metabolism*
  • Mice
  • Molecular Sequence Data
  • Translocation, Genetic
  • V(D)J Recombination


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • V(D)J recombination activating protein 2
  • RAG-1 protein
  • Ataxia Telangiectasia Mutated Proteins

Associated data

  • GEO/GSE69478