A Distinctive DNA Damage Response in Human Hematopoietic Stem Cells Reveals an Apoptosis-Independent Role for p53 in Self-Renewal

被引：227

作者：

Milyavsky, Michael ^{[1
,2
]}

Gan, Olga I. ^{[1
,2
]}

Trottier, Magan ^{[2
,5
]}

Komosa, Martin ^{[5
]}

Tabach, Ofer ^{[6
]}

Notta, Faiyaz ^{[1
,2
]}

Lechman, Eric ^{[1
,2
]}

Hermans, Karin G. ^{[1
,2
]}

Eppert, Kolja ^{[1
,2
]}

Konovalova, Zhanna ^{[1
,2
]}

Ornatsky, Olga ^{[3
]}

Domany, Eytan ^{[6
]}

Meyn, M. Stephen ^{[2
,4
,5
]}

Dick, John E. ^{[1
,2
]}

机构：

[1] Univ Toronto, Dept Stem Cell & Dev Biol, Campbell Family Canc Res Inst,Univ Hlth Network, Ontario Canc Inst,Toronto Gen Res Inst, Toronto, ON M5G 1L7, Canada

[2] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada

[3] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5G 1L7, Canada

[4] Univ Toronto, Dept Pediat, Toronto, ON M5G 1L7, Canada

[5] Hosp Sick Children, Res Inst, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[6] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel

来源：

CELL STEM CELL | 2010年 / 7卷 / 02期

关键词：

DOUBLE-STRAND BREAKS; RADIATION SENSITIVITY; MAMMALIAN-CELLS; REPAIR; VIVO; PHENOTYPE; EXPANSION; CULTURE; BLOOD; MICE;

D O I：

10.1016/j.stem.2010.05.016

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：186 / 197

页数：12

共 51 条

[1] Hematopoietic stem cells engraft in mice with absolute efficiency [J].