Zbtb1 Safeguards Genome Integrity and Prevents p53-Mediated Apoptosis in Proliferating Lymphoid Progenitors

Expression of the transcription factor Zbtb1 is required for normal lymphoid development. We report in the present study that Zbtb1 maintains genome integrity in immune progenitors, without which cells undergo increased DNA damage and p53-mediated apoptosis during replication and differentiation. In...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-08, Vol.197 (4), p.1199-1211
Main Authors: Cao, Xin, Lu, Ying, Zhang, Xianyu, Kovalovsky, Damian
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Blotting, Western
Cell Differentiation - immunology
Cell Proliferation - physiology
Cell Separation
Chromosomes, Artificial, Bacterial
DNA Damage - physiology
Flow Cytometry
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - immunology
Image Processing, Computer-Assisted
In Situ Nick-End Labeling
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Confocal
Polymerase Chain Reaction
Repressor Proteins - immunology
Tumor Suppressor Protein p53 - physiology
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Summary:Expression of the transcription factor Zbtb1 is required for normal lymphoid development. We report in the present study that Zbtb1 maintains genome integrity in immune progenitors, without which cells undergo increased DNA damage and p53-mediated apoptosis during replication and differentiation. Increased DNA damage in Zbtb1-mutant (ScanT) progenitors was due to increased sensitivity to replication stress, which was a consequence of inefficient activation of the S-phase checkpoint response. Increased p53-mediated apoptosis affected not only lymphoid but also myeloid development in competitive bone marrow chimeras, and prevention of apoptosis by transgenic Bcl2 expression and p53 deficiency rescued lymphoid as well as myeloid development from Zbtb1-mutant progenitors. Interestingly, however, protection from apoptosis rescued only the early stages of T cell development, and thymocytes remained arrested at the double-negative 3 developmental stage, indicating a strict requirement of Zbtb1 at later T cell developmental stages. Collectively, these results indicate that Zbtb1 prevents DNA damage in replicating immune progenitors, allowing the generation of B cells, T cells, and myeloid cells.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1600013