title: Sustained E2F-Dependent Transcription Is a Key Mechanism to Prevent Replication-Stress-Induced DNA Damage.
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.
authors.affiliation: MRC Laboratory for Molecular Cell Biology , University College London, London WC1E 6BT, UK.
authors.forename: Cosetta
authors.initials: C
authors.lastname: Bertoli
authors.affiliation: MRC Laboratory for Molecular Cell Biology , University College London, London WC1E 6BT, UK.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Herlihy
authors.affiliation: MRC Laboratory for Molecular Cell Biology , University College London, London WC1E 6BT, UK.
authors.forename: Betheney R
authors.initials: BR
authors.lastname: Pennycook
authors.affiliation: MRC Laboratory for Molecular Cell Biology , University College London, London WC1E 6BT, UK; Bioinformatics Image Core (BIONIC), University College London, London WC1E 6BT, UK.
authors.forename: Janos
authors.initials: J
authors.lastname: Kriston-Vizi
authors.affiliation: MRC Laboratory for Molecular Cell Biology , University College London, London WC1E 6BT, UK; The UCL Cancer Institute, University College London, London WC1E 6BT, UK. Electronic address: r.debruin@ucl.ac.uk.
authors.forename: Robertus A M
authors.initials: RAM
authors.lastname: de Bruin
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D050684:E2F Transcription Factors / Q000378:metabolism*; D006801:Humans; D009857:Oncogenes; D014176:Protein Biosynthesis / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D050684:E2F Transcription Factors