The recent advances in non-homologous end-joining through the lens of lymphocyte development

Lymphocyte development requires ordered assembly and subsequent modifications of the antigen receptor genes through V(D)J recombination and Immunoglobulin class switch recombination (CSR), respectively. While the programmed DNA cleavage events are initiated by lymphocyte-specific factors, the result...

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Bibliographic Details
Published in:DNA repair 2020-10, Vol.94, p.102874-102874, Article 102874
Main Authors: Wang, Xiaobin S., Lee, Brian J., Zha, Shan
Format: Article
Language:English
Subjects:
Animals
Ataxia Telangiectasia Mutated Proteins - metabolism
ATM
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Class switch recombination
DNA End-Joining Repair
DNA-Activated Protein Kinase - metabolism
DNA-PK
Humans
Immunoglobulin Class Switching
Non-homologous end-joining
V(D)J Recombination
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Summary:Lymphocyte development requires ordered assembly and subsequent modifications of the antigen receptor genes through V(D)J recombination and Immunoglobulin class switch recombination (CSR), respectively. While the programmed DNA cleavage events are initiated by lymphocyte-specific factors, the resulting DNA double-strand break (DSB) intermediates activate the ATM kinase-mediated DNA damage response (DDR) and rely on the ubiquitously expressed classical non-homologous end-joining (cNHEJ) pathway including the DNA-dependent protein kinase (DNA-PK), and, in the case of CSR, also the alternative end-joining (Alt-EJ) pathway, for repair. Correspondingly, patients and animal models with cNHEJ or DDR defects develop distinct types of immunodeficiency reflecting their specific DNA repair deficiency. The unique end-structure, sequence context, and cell cycle regulation of V(D)J recombination and CSR also provide a valuable platform to study the mechanisms of, and the interplay between, cNHEJ and DDR. Here, we compare and contrast the genetic consequences of DNA repair defects in V(D)J recombination and CSR with a focus on the newly discovered cNHEJ factors and the kinase-dependent structural roles of ATM and DNA-PK in animal models. Throughout, we try to highlight the pending questions and emerging differences that will extend our understanding of cNHEJ and DDR in the context of primary immunodeficiency and lymphoid malignancies.
ISSN:1568-7864
1568-7856
DOI:10.1016/j.dnarep.2020.102874