Document Detail

Dual functions of Nbs1 in the repair of DNA breaks and proliferation ensure proper V(D)J recombination and T-cell development.
MedLine Citation:
PMID:  20921278     Owner:  NLM     Status:  MEDLINE    
Immunodeficiency and lymphoid malignancy are hallmarks of the human disease Nijmegen breakage syndrome (NBS; OMIM 251260), which is caused by NBS1 mutations. Although NBS1 has been shown to bind to the T-cell receptor alpha (TCRα) locus, its role in TCRβ rearrangement is unclear. Hypomorphic mutations of Nbs1 in mice and patients result in relatively mild T-cell deficiencies, raising the question of whether the truncated Nbs1 protein might have clouded a certain function of NBS1 in T-cell development. Here we show that the deletion of the entire Nbs1 protein in T-cell precursors (Nbs1(T-del)) results in severe lymphopenia and a hindrance to the double-negative 3 (DN3)-to-DN4 transition in early T-cell development, due to abnormal TCRβ coding and signal joints as well as the functions of Nbs1 in T-cell expansion. Chromatin immunoprecipitation (ChIP) analysis of the TCR loci reveals that Nbs1 depletion compromises the loading of Mre11/Rad50 to V(D)J-generated DNA double-strand breaks (DSBs) and thereby affects resection of DNA termini and chromatin conformation of the postcleavage complex. Although a p53 deficiency relieves the DN3→DN4 transition block, neither a p53 deficiency nor ectopic expression of TCRαβ rescues the major T-cell loss in Nbs1(T-del) mice. All together, these results demonstrate that Nbs1's functions in both repair of V(D)J-generated DSBs and proliferation are essential for T-cell development.
Amal Saidi; Tangliang Li; Falk Weih; Patrick Concannon; Zhao-Qi Wang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-04
Journal Detail:
Title:  Molecular and cellular biology     Volume:  30     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-08     Completed Date:  2010-12-06     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5572-81     Citation Subset:  IM    
Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07743 Jena, Germany.
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MeSH Terms
Base Sequence
Cell Cycle Proteins / genetics*,  metabolism*
Cell Differentiation
Cell Proliferation
DNA Breaks
DNA Primers / genetics
DNA Repair / genetics*,  physiology*
Disease Models, Animal
Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor
Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
Genes, Immunoglobulin Heavy Chain*
Genes, p53
Lymphopenia / genetics,  immunology,  metabolism
Mice, Knockout
Nijmegen Breakage Syndrome / genetics,  immunology,  metabolism
Nuclear Proteins / deficiency,  genetics*,  metabolism*
Recombination, Genetic
T-Lymphocytes / cytology,  immunology*,  metabolism*
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA Primers; 0/NBN protein, human; 0/Nijmegen breakage syndrome 1 protein, mouse; 0/Nuclear Proteins

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