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Abstract
Three main cell death phenotypes have been identified in mammalian systems: apoptosis, autophagy and programmed necrosis. Currently, the field lacks systems level approaches to assess how the intricate cross-talk and interconnectivity between the different death functional modules affect the cell's final outcome. In order to dissect the cell death network's architecture, we developed a platform that measures the outcome of single and double RNAi-mediated perturbations of different apoptotic and autophagic genes on both the final cell death performance, and the pattern of protein connectivity. We applied this platform on cells exposed to a DNA damaging drug, and identified several levels of connectivity between apoptosis and autophagy. In addition, using computational methods we suggested a novel biochemical pathway providing a connection between ATG5 and caspase-3. Scaling up this platform into hundreds of perturbations will reveal novel principles of the organization of the cell death network, and will provide the basis for future computational modeling.