Integrated signaling in developing lymphocytes: The role of DNA damage responses

Jeffrey J. Bednarski, Barry P. Sleckman

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

Lymphocyte development occurs in a stepwise progression through distinct developmental stages. This ordered maturation ensures that cells express a single, non-autoreactive antigen receptor, which is the cornerstone of a diverse adaptive immune response. Expression of a mature antigen receptor requires assembly of the antigen receptor genes by the process of V(D)J recombination, a reaction that joins distant gene segments through DNA double-strand break (DSB) intermediates. These physiologic DSBs are generated by the recombinase- activating gene (RAG) -1 and -2 proteins, and their generation is regulated by lymphocyte and developmental stage-specific signals from cytokine receptors and antigen receptor chains. Collectively, these signals ensure that V(D)J recombination of specific antigen receptor genes occurs at discrete developmental stages. Once generated, RAG-induced DSBs activate the ataxia-telangiectasia mutated (ATM) kinase to orchestrate a multifaceted DNA damage response that ensures proper DSB repair. In response to RAG DSBs, ATM also regulates a cell type-specific transcriptional response, and here we discuss how this genetic program integrates with other cellular cues to regulate lymphocyte development.

Original languageEnglish
Pages (from-to)4129-4134
Number of pages6
JournalCell Cycle
Volume11
Issue number22
DOIs
StatePublished - Nov 15 2012

Keywords

  • Development
  • Interleukin-7
  • Lymphocyte
  • NFκB
  • Pim2
  • Pre-BCR
  • RAG
  • Survival
  • V(D)J recombination

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