Journal
CELL CYCLE
Volume 11, Issue 22, Pages 4129-4134Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.22021
Keywords
RAG; lymphocyte; survival; development; NF kappa B; Pim2; interleukin-7; pre-BCR; V(D)J recombination
Categories
Funding
- National Institutes of Health [CA136470, AI074953, AI47829]
- Hyundai Hope on Wheels Scholar Award
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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.
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