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Articles

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

Halfdan Beck, Viola Nähse-Kumpf, Marie Sofie Yoo Larsen, Karen A. O'Hanlon, Sebastian Patzke, Christian Holmberg, Jakob Mejlvang, Anja Groth, Olaf Nielsen, Randi G. Syljuåsen, Claus Storgaard Sørensen
Halfdan Beck
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Viola Nähse-Kumpf
Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Marie Sofie Yoo Larsen
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Karen A. O'Hanlon
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Sebastian Patzke
Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Christian Holmberg
Department of Biology, University of Copenhagen, Copenhagen, Denmark
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Jakob Mejlvang
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Anja Groth
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Olaf Nielsen
Department of Biology, University of Copenhagen, Copenhagen, Denmark
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Randi G. Syljuåsen
Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Claus Storgaard Sørensen
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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DOI: 10.1128/MCB.00412-12
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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.

FOOTNOTES

    • Received 28 March 2012.
    • Returned for modification 24 April 2012.
    • Accepted 7 August 2012.
    • Accepted manuscript posted online 20 August 2012.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00412-12.

  • Copyright © 2012, American Society for Microbiology. All Rights Reserved.
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Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption
Halfdan Beck, Viola Nähse-Kumpf, Marie Sofie Yoo Larsen, Karen A. O'Hanlon, Sebastian Patzke, Christian Holmberg, Jakob Mejlvang, Anja Groth, Olaf Nielsen, Randi G. Syljuåsen, Claus Storgaard Sørensen
Molecular and Cellular Biology Sep 2012, 32 (20) 4226-4236; DOI: 10.1128/MCB.00412-12

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Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption
Halfdan Beck, Viola Nähse-Kumpf, Marie Sofie Yoo Larsen, Karen A. O'Hanlon, Sebastian Patzke, Christian Holmberg, Jakob Mejlvang, Anja Groth, Olaf Nielsen, Randi G. Syljuåsen, Claus Storgaard Sørensen
Molecular and Cellular Biology Sep 2012, 32 (20) 4226-4236; DOI: 10.1128/MCB.00412-12
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