c-Myc oncogenic activity is thought to be mediated in part by its ability to generate DNA replication stress and subsequent genomic instability when deregulated. Previous studies have demonstrated a nontranscriptional role for c-Myc in regulating DNA replication. Here, we analyze the mechanisms by which c-Myc deregulation generates DNA replication stress. We find that overexpression of c-Myc alters the spatiotemporal program of replication initiation by increasing the density of early-replicating origins. We further show that c-Myc deregulation results inelevated replication-fork stalling or collapse and subsequent DNA damage. Notably, these phenotypes are independent of RNA transcription. Finally, we demonstrate that overexpression of Cdc45 recapitulates all c-Myc-induced replication and damage phenotypes and that Cdc45 and GINS function downstream of Myc. © 2013 The Authors.
Srinivasan, S. V., Dominguez-Sola, D., Wang, L. C., Hyrien, O., & Gautier, J. (2013). Cdc45 Is a Critical Effector of Myc-Dependent DNA Replication Stress. Cell Reports, 3(5), 1629–1639. https://doi.org/10.1016/j.celrep.2013.04.002