The definition of an oncogene is a gene that actively promotes tumorigenesis. For example, activation of RAS oncogene promotes cell transformation and cancer. Paradoxically, in primary mammalian cells, oncogenic RAS typically triggers cellular senescence, a state of irreversible cell growth arrest. Oncogene-induced senescence is an important tumor suppression mechanism in vivo. Here, we discuss our recent evidence that RAS-induced suppression of DNA repair response via dissociation of BRCA1 from chromatin promotes senescence while predisposing cells to senescence bypass and transformation by allowing for secondary hits. The molecular mechanism we uncovered helps reconcile the tumor-promoting nature of oncogenic RAS with the tumor-suppressing role of oncogene-induced senescence.
Z Tu, KM Aird, BG Bitler, JP Nicodemus, N Beeharry, B Xia, TJ Yen, R Zhang. Oncogenic RAS regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence. Dev Cell 2011; 21: 1077- 91.