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Cdc45 is a critical effector of myc-dependent DNA replication stress.

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.

SUBMITTER: Srinivasan SV

PROVIDER: S-EPMC3822004 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Cdc45 is a critical effector of myc-dependent DNA replication stress.

Srinivasan Seetha V SV Dominguez-Sola David D Wang Lily C LC Hyrien Olivier O Gautier Jean J

Cell reports 20130502 5

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-replicatin ...[more]

PMID: 23643534

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