Lymphocyte Development: Integration of DNA Damage Response Signaling

Lymphocytes traverse functionally discrete stages as they develop into mature B and T cells. This development is directed by cues from a variety of different cell surface receptors. To complete development, all lymphocytes must express a functional nonautoreactive heterodimeric antigen receptor. The genes that encode antigen receptor chains are assembled through the process of V(D)J recombination, a reaction that proceeds through DNA double-stranded break (DSB) intermediates. These DSBs are generated by the RAG endonuclease in G1-phase developing lymphocytes and activate ataxia-telangiectasia mutated (ATM), the kinase that orchestrates cellular DSB responses. The canonical DNA damage response includes cell cycle arrest, DNA break repair, and apoptosis of cells when DSBs are not repaired. However, recent studies have demonstrated that ATM activation in response to RAG DSBs also regulates a transcriptional program including many genes with no known function in canonical DNA damage responses. Rather, these genes have activities that would be important for lymphocyte development. Here, these findings and the broader concept that signals initiated by physiologic DNA DSBs provide cues that regulate cell type-specific processes and functions are discussed.