Document Detail

Integrated signaling in developing lymphocytes: the role of DNA damage responses.
MedLine Citation:
PMID:  23032308     Owner:  NLM     Status:  MEDLINE    
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.
Jeffrey J Bednarski; Barry P Sleckman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-20     Completed Date:  2013-04-30     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4129-34     Citation Subset:  IM    
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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
Lymphocytes / immunology,  metabolism*
Nuclear Proteins / metabolism
Pre-B Cell Receptors / metabolism
Precursor Cells, B-Lymphoid / immunology,  metabolism
Protein-Serine-Threonine Kinases / metabolism
Receptors, Interleukin-7 / metabolism
Signal Transduction
Tumor Suppressor Proteins / metabolism
V(D)J Recombination
Grant Support
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Homeodomain Proteins; 0/Nuclear Proteins; 0/Pre-B Cell Receptors; 0/RAG2 protein, human; 0/Receptors, Interleukin-7; 0/Tumor Suppressor Proteins; 128559-51-3/RAG-1 protein; EC protein, human; EC Telangiectasia Mutated Proteins; EC Kinases

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