Cdc45 Is a Critical Effector of Myc-Dependent DNA Replication Stress

• Myc alters the spatiotemporal pattern of DNA replication initiation
• Myc triggers DNA replication fork stalling
• Myc-dependent DNA replication phenotypes require Cdc45 and GINS
• Myc-dependent DNA damage requires Cdc45

Summaryc-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 in elevated 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.

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