DNA damage: An inherent flaw of apoptosis-mediated tumour suppression?
Session type: Parallel sessions
Mitochondria are often essential for apoptosis through a process termed mitochondrial outer membrane permeabilisation or MOMP. This event leads to robust activation of caspase proteases and rapid cell death. Originally regarded as an all-or-nothing event, we have previously found that some mitochondria can evade MOMP and allow cell survival when caspase activity is blocked. From this, we have been interested in whether the converse happens - can limited mitochondrial permeabilisation occur and, if so, what are its consequences? Utilising a microscopy-based approach, we find that novel, apoptosis-engaging chemotherapeutics - termed BH3-mimetics - can induce mitochondrial-permeabilisation in a limited cohort of mitochondria. However, rather than triggering cell death, limited mitochondrial permeabilisation leads to caspase-dependent, nuclear DNA damage. Significantly, we find that non-lethal engagement of MOMP can also trigger DNA damage in various tissues in vivo. Importantly, using a novel method to mimic 'primed-to-die' cancer cells, we find that BH3-only proteins themselves govern cellular sensitivity to MOMP induced DNA damage. These results argue that failure to properly execute mitochondrial-dependent apoptosis leads to DNA damage. Besides having important implications for apoptosis-mediated tumour suppression, our findings also provide the basis for new ways to manipulate apoptosis in a therapeutic context.