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

Academic Article

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. © 2012 Landes Bioscience.
  • Authors

    Published In

  • Cell Cycle  Journal
  • Digital Object Identifier (doi)

    Author List

  • Bednarski JJ; Sleckman BP
  • Start Page

  • 4129
  • End Page

  • 4134
  • Volume

  • 11
  • Issue

  • 22