DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions

DNA damage leads to a halt in proliferation owing to apoptosis or senescence, which prevents transmission of DNA alterations. This cellular response depends on the tumor suppressor p53 and functions as a powerful barrier to tumor development. Adult stem cells are resistant to DNA damage-induced apoptosis or senescence, however, and how they execute this response and suppress tumorigenesis is unknown. We show that irradiation of hematopoietic and mammary stem cells up-regulates the cell cycle inhibitor p21, a known target of p53, which prevents p53 activation and inhibits p53 basal activity, impeding apoptosis and leading to cell cycle entry and symmetric self-renewing divisions. p21 also activates DNA repair, limiting DNA damage accumulation and self-renewal exhaustion. Stem cells with moderate DNA damage and diminished self-renewal persist after irradiation, however. These findings suggest that stem cells have evolved a unique, p21-dependent response to DNA damage that leads to their immediate expansion and limits their long-term survival.Adult stem cells (SCs) are thought to be resistant to DNA damage (DD)-induced apoptosis or senescence owing to the activation of unique pro-survival and DD repair (DDR) responses (1–3). Genetic alterations that decrease DNA repair activities lead to increased DD and reduced self-renewal in SCs, suggesting that DDR is critical to preservation of SC function (1, 4, 5). DDR decreases during physiological aging, a phenomenon correlated with the accumulation of endogenous DD and decreased self-renewal in aged SCs (6–9).In differentiated cells, DD triggers a checkpoint response that leads to apoptosis or senescence and depends on activation of the tumor suppressor p53 (10). This is considered a powerful tumor-suppressor mechanism, as demonstrated by the finding that p53 is invariably inactivated in spontaneous tumors (11). After irradiation, p53 is up-regulated in populations enriched for hematopoietic, hair follicle bulge, and colon SCs (5, 12–15). Whether this is critical for activation of the DDR response and maintenance of self-renewal, why p53 induction does not result in SC apoptosis or senescence, and how tumor suppression is executed in SCs remain unclear, however. Indirect evidence indicates that the cell cycle inhibitor p21, a downstream effector of p53, might be involved in DD processing in SCs. In the absence of p21, SCs exhaust prematurely (16) and after a low radiation dose display reduced reconstitution capacity (17). Here we report our studies on the role of p53 and p21 in DD processing of highly purified hematopoietic SCs (HSCs) and mammary SCs (MaSCs).