Genome-Wide Loss-of-Function Genetic Screens Identify Novel Senescence Genes and Putative Tumor Suppressors

During every cell cycle and upon exogenous stress, tumor suppression programs are engaged to ensure genomic stability. In response to replicative aging and oncogenic stimuli, the p53 and Rb pathways are activated to prevent the proliferation of damaged cells. Several lines of evidence suggest that escape from senescence is a crucial early step in oncogenic progression. A major challenge in the cancer field is to combine genomic information regarding cancer-associated genetic changes with high-throughput functional studies, in order to confirm genetic requirements and pinpoint biological roles of these perturbed genes in oncogenesis. Furthermore, a complete genetic understanding of replicative senescence, and how it might be bypassed, is lacking. We describe here two genome scale loss-of-function genetic screens that interrogate these tumor suppressor programs. We utilized a unique sensitization approach to isolate senescence pathways and unmask compensatory mechanisms that may have been difficult to identify in previous studies. These genetic screens have generated comprehensive and validated datasets of putative senescence and p53 pathway genes. We present this dataset as a high-quality resource for further investigation into these biological pathways.