Are DNA lesions sufficient to trigger apoptosis?
The p53-dependent pathway which induces apoptotic cell death in response to DNA damage is clearly relevant in terms of cancer therapy toxicity, since normal tissues exposed to DNA damage can undergo apoptosis. Stabilization of p53 following DNA damage results in its accumulation in both nuclear and cytosolic compartments. Cytosolic p53 can directly activate the proapoptotic activity of Bax to permeabilize the mitochondrial outer membrane. It remains to be determined to what extent this cytosolic effect, independent of transcription, contributes to p53-mediated death. If cytosolic p53 is apoptotic, the transcriptional upregulation of PUMA may provide another block to the anti-apoptotic functions of Bcl-2/Bcl-xl. However, in most solid tumors these pathways are unlikely to contribute to DNA damage-induced death, because in most tumors p53 is inactivated by mutations. Therefore it is anticipated that inhibiting p53-dependent apoptosis may enhance the therapeutic index of cancer therapy, a
