期刊
CELL STEM CELL
卷 7, 期 2, 页码 186-197出版社
CELL PRESS
DOI: 10.1016/j.stem.2010.05.016
关键词
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资金
- European Molecular Biology Organization (EMBO)
- European Hematology Association
- The Netherland Society for Scientific Research (NOW)
- The Stem Cell Network of National Centers of Excellence
- Canadian Cancer Society Research Institute
- Terry Fox Foundation
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- Premier's Summit Award funded from the province of Ontario
- Leukemia and Lymphoma Society
- Canadian Institutes for Health Research (CHIR)
- Canada Research Chair
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
Highly regenerative tissues such as blood must possess effective DNA damage responses (DDR) that balance long-term regeneration with protection from leukemogenesis. Hematopoietic stem cells (HSCs) sustain life-long blood production, yet their response to DNA damage remains largely unexplored. We report that human HSCs exhibit delayed DNA double-strand break rejoining, persistent gamma H2AX foci, and enhanced p53- and ASPP1-dependent apoptosis after gamma-radiation compared to progenitors. p53 inactivation or Bcl-2 overexpression reduced radiation-induced apoptosis and preserved in vivo repopulating HSC function. Despite similar protection from irradiation-induced apoptosis, only Bcl-2-overexpressing HSCs showed higher self-renewal capacity, establishing that intact p53 positively regulates self-renewal independently from apoptosis. The reduced self-renewal of HSCs with inactivated p53 was associated with increased spontaneous gamma H2AX foci in secondary transplants of HSCs. Our data reveal distinct physiological roles of p53 that together ensure optimal HSC function: apoptosis regulation and prevention of gamma H2AX foci accumulation upon HSC self-renewal.
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