DNA replication stress and cancer
Genomic instability is one of the most important factors driving cancer progression and resistance to therapy. Oncogenes, by inducing DNA replication stress, are a critical factor underlying genomic instability in cancer, but the mechanisms by which oncogenes cause DNA replication stress have remained largely elusive. A major impediment has been mapping DNA replication initiation sites in the human genome, which is a prerequisite for understanding how oncogenes affect DNA replication. In this study, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the oncogenes CCNE1 or MYC. Remarkably, both oncogenes induced the firing of many novel, overlapping DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase due to oncogene activation allowed origin firing within genic regions that had not yet been transcribed. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-strand break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of ectopic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
Department of Molecular Biology, University of Geneva, Switzerland
Directeur de recherche CNRS
Domain 2 - UMR 3244 - Dynamics of genetic Information