Abstract
Recent work established DNA replication stress as a crucial driver of genomic instability and a key event at the onset of cancer. Post-translational modifications play an important role in the cellular response to replication stress by regulating the activity of key components to prevent replication-stress-induced DNA damage. Here, we establish a far greater role for transcriptional control in determining the outcome of replication-stress-induced events than previously suspected. Sustained E2F-dependent transcription is both required and sufficient for many crucial checkpoint functions, including fork stalling, stabilization, and resolution. Importantly, we also find that, in the context of oncogene-induced replication stress, where increased E2F activity is thought to cause replication stress, E2F activity is required to limit levels of DNA damage. These data suggest a model in which cells experiencing oncogene-induced replication stress through deregulation of E2F-dependent transcription become addicted to E2F activity to cope with high levels of replication stress.