Journal
CELL REPORTS
Volume 3, Issue 5, Pages 1629-1639Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.04.002
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Funding
- National Institutes of Health [CA92245, CA167826, 5K99 CA151827]
- US Department of Defense [W81XWH-09-1-0504]
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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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