title: Integrated signaling in developing lymphocytes: the role of DNA damage responses.
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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Bednarski
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D054420:Pre-B Cell Receptors / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D054420:Pre-B Cell Receptors; C499311:RAG2 protein, human; D020395:Receptors, Interleukin-7; D025521:Tumor Suppressor Proteins; C064658:RAG-1 protein; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases