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

Seetha V. Srinivasan; David Dominguez-Sola; Lily C. Wang; Olivier Hyrien; Jean Gautier

doi:10.1016/j.celrep.2013.04.002

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

Seetha V. Srinivasan, David Dominguez-Sola, Lily C. Wang, Olivier Hyrien, Jean Gautier

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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 inelevated 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.

Original language	English
Pages (from-to)	1629-1639
Number of pages	11
Journal	Cell Reports
Volume	3
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2013.04.002
State	Published - 30 May 2013
Externally published	Yes

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@article{46ed942fcdf54a8ea3ebbc4dd71bc90b,

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 inelevated 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.",

author = "Srinivasan, {Seetha V.} and David Dominguez-Sola and Wang, {Lily C.} and Olivier Hyrien and Jean Gautier",

note = "Funding Information: We thank Dr. J. Walter from Harvard Medical School for generously providing the Cdc45 antibody; Dr. J. Mendez from Spanish National Cancer Research Centre for the generous gift of the GINS proteins and antibodies, Dr. R. Yew for p27Xic1 construct, Drs. C. Ying, A. Sfeir and T. Aparicio for helpful discussions; Drs. T. Swayne and A. White for help with Microscopy/data analysis; members of the Hyrien laboratory for training and advice on the DNA-combing technique. We gratefully acknowledge funding support from the National Institutes of Health (CA92245 and CA167826) to J.G., (5K99 CA151827) to D.D.-S. and the US Department of Defense (W81XWH-09-1-0504) to S.V.S. ",

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doi = "10.1016/j.celrep.2013.04.002",

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AU - Srinivasan, Seetha V.

AU - Dominguez-Sola, David

AU - Wang, Lily C.

AU - Hyrien, Olivier

AU - Gautier, Jean

N1 - Funding Information: We thank Dr. J. Walter from Harvard Medical School for generously providing the Cdc45 antibody; Dr. J. Mendez from Spanish National Cancer Research Centre for the generous gift of the GINS proteins and antibodies, Dr. R. Yew for p27Xic1 construct, Drs. C. Ying, A. Sfeir and T. Aparicio for helpful discussions; Drs. T. Swayne and A. White for help with Microscopy/data analysis; members of the Hyrien laboratory for training and advice on the DNA-combing technique. We gratefully acknowledge funding support from the National Institutes of Health (CA92245 and CA167826) to J.G., (5K99 CA151827) to D.D.-S. and the US Department of Defense (W81XWH-09-1-0504) to S.V.S.

PY - 2013/5/30

Y1 - 2013/5/30

N2 - 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 inelevated 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.

AB - 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 inelevated 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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VL - 3

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JO - Cell Reports

JF - Cell Reports

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

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