FIGURE 8.

Proposed molecular pathways for the induction of apoptotic Top1cc by TRAIL. The binding of TRAIL to its DR4 and DR5 receptors activates the Bax-dependent mitochondrial death pathway, causing caspase-3 activation, and accumulation of ROS. The mitochondrial pathway can be activated directly by the BH3 mimetics antimycin A and BH3I-2′. Activated caspase-3 cleaves Top1 and generates ROS, which produce oxidative DNA lesions (8-oxoguanine, abasic sites, and strand breaks). Caspase-cleaved Top1 binds at the proximity of oxidative DNA lesions by forming apoptotic Top1cc (suicide complexes). Those complexes participate in apoptotic-related nuclear modifications including nuclear fission and the release of nuclear bodies in the extracellular space and may therefore contribute to the recognition and elimination of apoptotic cells.