The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence

Cytotoxic chemotherapy is intended to eliminate transformed cells but can also provoke therapy-induced senescence, a persistent and pro-inflammatory cell state that can promote tumor progression. The molecular mechanisms that govern the apoptosis-senescence fate decision remain incompletely understood. Here, we show that the mitochondrial pore-forming proteins BAX and BAK function as a critical checkpoint that restricts entry to therapy-induced senescence. Genetic ablation of BAX and BAK markedly enhanced entry to senescence in response to multiple DNA-damaging agents, whereas loss of the BAX/BAK antagonists Bcl-xL or Mcl-1 suppressed entry to senescence and promoted cell death. Mechanistically, genotoxic stress induced BH3-only proteins, including Noxa, Bid, and Puma, creating a dependence on Bcl-xL and Mcl-1 to restrain BAX/BAK activation and maintain survival. These findings identify the Bcl-2 family network as a central regulator of entry to therapy-induced senescence, a pro-inflammatory cell state that goes beyond the mere avoidance of apoptosis.