title: Mechanisms of oncogene-induced genomic instability.
abstract: Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre-neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means. Although the molecular mechanisms by which OIS is established are not totally understood, the current view is that OIS in human cells is tightly linked to persistent activation of the DNA damage response (DDR) pathway, as a consequence of replication stress. Here we will highlight recent advances in our understanding of molecular mechanisms leading to hyper-replication stress in response to oncogene activation, and of the crosstalk between replication stress and persistent activation of the DDR. We will also discuss new evidence for DNA repair deficiencies during OIS, which might increase the genomic instability that drives senescence bypass and malignant transformation.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Graziano
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: sgonzalo@slu.edu.
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D016922:Cellular Senescence; D004249:DNA Damage; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D009857:Oncogenes / Q000502:physiology*