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. We have uncovered several genes in distinct biological pathways which have not been demonstrated to have a functional role in senescence, and which may be putative tumor suppressors. We have identified BRD7 and BAF180, two SWI/SNF components, as critical regulators of p53. BRD7 and BAF180 are required for p53 activity and p21 expression during replicative and oncogene-induced senescence, and evidence suggests that they are inactivated in human cancer. In addition, we have uncovered a role for the deubiquitinating enzyme USP28 in the regulation of p53 accumulation during senescence, such that loss of USP28 results in bypass of the senescence program. We have also investigated several other novel senescence genes including SEMA6A, SEMA3b, and TMEM154. We have found that the expression of these genes is highly regulated during senescence by distinct means, including both p53-dependent and p53-independent mechanisms. These results demonstrate the efficacy of our sensitized screening approach, and also highlight the emerging view that the senescence program requires the combined action of multiple biological pathways for its execution.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/10330320 |
| Date | January 2012 |
| Creators | Burrows, Anna |
| Contributors | Elledge, Stephen J. |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | closed access |
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