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

Cell Cycle. 2012 Nov 15;11(22):4129-34. doi: 10.4161/cc.22021. Epub 2012 Oct 3.

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.

Publication types

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

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA Repair
  • DNA-Binding Proteins / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Lymphocytes / immunology
  • Lymphocytes / metabolism*
  • Nuclear Proteins / metabolism
  • Pre-B Cell Receptors / metabolism
  • Precursor Cells, B-Lymphoid / immunology
  • Precursor Cells, B-Lymphoid / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Interleukin-7 / metabolism
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism
  • V(D)J Recombination

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Nuclear Proteins
  • Pre-B Cell Receptors
  • RAG2 protein, human
  • Receptors, Interleukin-7
  • Tumor Suppressor Proteins
  • RAG-1 protein
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases