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Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption

Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of... Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption Halfdan Beck a , Viola Nähse-Kumpf b , Marie Sofie Yoo Larsen a , Karen A. O'Hanlon a , Sebastian Patzke b , Christian Holmberg c , Jakob Mejlvang a , Anja Groth a , Olaf Nielsen c , Randi G. Syljuåsen b and Claus Storgaard Sørensen a a Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark b Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway c Department of Biology, University of Copenhagen, Copenhagen, Denmark ABSTRACT Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood. We now show that elevation of CDK activity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduled CDK activity on fork speed and DNA DSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulated CDK activity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular and Cellular Biology American Society For Microbiology

Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption

Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption

Molecular and Cellular Biology , Volume 32 (20): 4226 – Oct 15, 2012

Abstract

Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption Halfdan Beck a , Viola Nähse-Kumpf b , Marie Sofie Yoo Larsen a , Karen A. O'Hanlon a , Sebastian Patzke b , Christian Holmberg c , Jakob Mejlvang a , Anja Groth a , Olaf Nielsen c , Randi G. Syljuåsen b and Claus Storgaard Sørensen a a Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark b Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway c Department of Biology, University of Copenhagen, Copenhagen, Denmark ABSTRACT Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood. We now show that elevation of CDK activity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduled CDK activity on fork speed and DNA DSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulated CDK activity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage.

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References (46)

Publisher
American Society For Microbiology
Copyright
Copyright © 2012 by the American society for Microbiology.
ISSN
0270-7306
eISSN
1098-5549
DOI
10.1128/MCB.00412-12
pmid
22907750
Publisher site
See Article on Publisher Site

Abstract

Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption Halfdan Beck a , Viola Nähse-Kumpf b , Marie Sofie Yoo Larsen a , Karen A. O'Hanlon a , Sebastian Patzke b , Christian Holmberg c , Jakob Mejlvang a , Anja Groth a , Olaf Nielsen c , Randi G. Syljuåsen b and Claus Storgaard Sørensen a a Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark b Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway c Department of Biology, University of Copenhagen, Copenhagen, Denmark ABSTRACT Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood. We now show that elevation of CDK activity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduled CDK activity on fork speed and DNA DSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulated CDK activity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage.

Journal

Molecular and Cellular BiologyAmerican Society For Microbiology

Published: Oct 15, 2012

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