The response to and repair of RAG-mediated DNA double-strand breaks

Beth A. Helmink, Barry P. Sleckman

Research output: Contribution to journalReview articlepeer-review

151 Scopus citations


Developing lymphocytes must assemble antigen receptor genes encoding the B cell and T cell receptors. This process is executed by the V(D)J recombination reaction, which can be divided into DNA cleavage and DNA joining steps. The former is carried out by a lymphocyte-specific RAG endonuclease, which mediates DNA cleavage at two recombining gene segments and their flanking RAG recognition sequences. RAG cleavage generates four broken DNA ends that are repaired by nonhomologous end joining forming coding and signal joints. On rare occasions, these DNA ends may join aberrantly forming chromosomal lesions such as translocations, deletions and inversions that have the potential to cause cellular transformation and lymphoid tumors. We discuss the activation of DNA damage responses by RAG-induced DSBs focusing on the component pathways that promote their normal repair and guard against their aberrant resolution. Moreover, we discuss how this DNA damage response impacts processes important for lymphocyte development.

Original languageEnglish
Pages (from-to)175-202
Number of pages28
JournalAnnual Review of Immunology
StatePublished - Apr 2012


  • Antigen receptor genes
  • DNA damage responses
  • Genomic stability
  • Lymphocyte development
  • Lymphoid tumors


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