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

SummaryHighly 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 γH2AX foci, and enhanced p53- and ASPP1-dependent apoptosis after γ-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 γH2AX 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 γH2AX foci accumulation upon HSC self-renewal.

► Irradiation induces a distinct DNA damage response in HSCs compared to progenitors
► Irradiation-induced p53-, ASPP1-, and Bcl-2-mediated apoptosis inhibits HSC activity
► p53 and Bcl-2 regulate HSC self-renewal potential
► Apoptosis-independent functions of p53 are required for optimal HSC self-renewal