MOLECULAR DISSECTION OF THE CROSSTALK BETWEEN ONCOGENIC AND TUMOR SUPPRESSIVE PATHWAYS: THE CASE OF TAZ-BRCA1 AND MYC-SETX GENETIC INTERACTIONS

Oncogenic and tumor suppressive pathways drive tumor evolution and define genetic liabilities of cancer cells. The investigation of these interactions may reveal novel therapeutic targets that can be exploited in clinics for the selective eradication of cancer cells. With this purpose, we investigated by genetic analysis the role of the tumor suppressor BRCA1 in repressing the activity of the TAZ oncogene. We characterized a post-translational regulatory mechanism based on the control of TAZ stability/degradation through BRCA1-mediated ubiquitination. This interplay may potentially explain the aggressive features of basal-like tumors, which are characterized by the co-occurrence of BRCA1 loss-of-function mutations and TAZ over-activation. We also looked at mechanisms required to maintain genome stability in Myc-driven tumors. We found that interfering with the resolution of transient transcriptional intermediates exacerbated lethal transcription-replication conflicts and enhanced replication stress to cytotoxic levels, thus triggering accumulation of DNA damage and cell death in cells challenged with oncogenic levels of Myc. Therefore, we unveiled a novel vulnerability of Myc-overexpressing cells, which require to coordinate transcriptional and replication dynamics to support Myc oncogenic activity.