Tissue regenerative delays and synthetic lethality in adult mice upon combined deletion of ATR and p53

Trp53 (p53) loss of function has previously been shown to rescue tissue maintenance and developmental defects resulting from DNA damage or DNA repair gene mutations1–12. Herein, we report that p53 deficiency significantly exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator ATR. Combined loss of ATR and p53 (p53(−/−)ATR(mKO)) led to severe defects in hair follicle regeneration, localized inflammation (Mac1(+)Gr1(+) infiltrates), accelerated deterioration of the intestinal epithelium, and synthetic lethality in adult mice. Tissue degeneration in p53(−/−)ATR(mKO) mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated presence of these damaged cells in both progenitor and downstream compartments in the skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. Together, our results indicate that combined loss of ATR and p53 in adult mice leads to the accumulation of highly damaged cells, which consequently impose a barrier to regeneration from undamaged progenitors.