title: Zbtb1 Safeguards Genome Integrity and Prevents p53-Mediated Apoptosis in Proliferating Lymphoid Progenitors.
abstract: 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.
authors.affiliation: College of Life Science and Engineering, Northwest University for Nationalities, Lanzhou 730030, China; and Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xin
authors.identifier: 0000-0001-6512-9233
authors.initials: X
authors.lastname: Cao
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ying
authors.identifier: 0000-0002-0962-8588
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xianyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 kovalovskyd@mail.nih.gov.
authors.forename: Damian
authors.initials: D
authors.lastname: Kovalovsky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation / Q000502:physiology; D002469:Cell Separation; D022202:Chromosomes, Artificial, Bacterial; D004249:DNA Damage / Q000502:physiology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D007091:Image Processing, Computer-Assisted; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C571129:ZBTB1 protein, mouse