title: 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.
authors: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors: Seetha V
authors: SV
authors: Srinivasan
authors: David
authors: D
authors: Dominguez-Sola
authors: Lily C
authors: LC
authors: Wang
authors: Olivier
authors: O
authors: Hyrien
authors: Jean
authors: J
authors: Gautier
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D006657:Histones / Q000378:metabolism; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus / Q000254:growth & development / Q000378:metabolism
chemical_list: C491876:Cdc45 protein, mouse; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27
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