A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal.
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 gammaH2AX 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 gammaH2AX 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 gammaH2AX foci accumulation upon HSC self-renewal.
Milyavsky
Michael
M
Department of Stem Cell and Developmental Biology, University of Toronto, Toronto, ON M5G 1L7, Canada.
Gan
Olga I
OI
Trottier
Magan
M
Komosa
Martin
M
Tabach
Ofer
O
Notta
Faiyaz
F
Lechman
Eric
E
Hermans
Karin G
KG
Eppert
Kolja
K
Konovalova
Zhanna
Z
Ornatsky
Olga
O
Domany
Eytan
E
Meyn
M Stephen
MS
Dick
John E
JE
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019070:Cell Lineage / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D019610:Cytoprotection / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D038042:Myelopoiesis / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011839:Radiation, Ionizing; D011995:Recombination, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498406:PPP1R13B protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53