Mol._Cell._Biol.-2010-Saidi-5572-81.pdf (2.02 MB)
Dual functions of Nbs1 in the repair of DNA breaks and proliferation ensure proper V(D)J recombination and T-cell development
journal contribution
posted on 2023-06-08, 05:12 authored by Amal Saidi, T Li, P Concannon, Z-Q WangImmunodeficiency 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 (TCRa) locus, its role in TCRß 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 TCRß 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 TCRaß rescues the major T-cell loss in Nbs1T-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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
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- Published version
Journal
Molecular and Cellular BiologyISSN
02707306Publisher
American Society for MicrobiologyExternal DOI
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23Volume
30Page range
5572-5581Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
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- Yes
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2012-02-06First Open Access (FOA) Date
2016-03-22First Compliant Deposit (FCD) Date
2016-11-16Usage metrics
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