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Cell Rep
2013 May 30;35:1629-39. doi: 10.1016/j.celrep.2013.04.002.
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Cdc45 is a critical effector of myc-dependent DNA replication stress.
Srinivasan SV
,
Dominguez-Sola D
,
Wang LC
,
Hyrien O
,
Gautier J
.
???displayArticle.abstract??? 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 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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