RAG Represents a Widespread Threat to the Lymphocyte Genome

Grace Teng, Yaakov Maman, Wolfgang Resch, Min Kim, Arito Yamane, Jason Qian, Kyong Rim Kieffer-Kwon, Malay Mandal, Yanhong Ji, Eric Meffre, Marcus R. Clark, Lindsay G. Cowell, Rafael Casellas, David G. Schatz

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53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)751-765
Number of pages15
JournalCell
Volume162
Issue number4
DOIs
StatePublished - Nov 11 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Teng, G., Maman, Y., Resch, W., Kim, M., Yamane, A., Qian, J., Kieffer-Kwon, K. R., Mandal, M., Ji, Y., Meffre, E., Clark, M. R., Cowell, L. G., Casellas, R., & Schatz, D. G. (2014). RAG Represents a Widespread Threat to the Lymphocyte Genome. Cell, 162(4), 751-765. https://doi.org/10.1016/j.cell.2015.07.009