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

Author:

Beck Halfdan1,Nähse-Kumpf Viola2,Larsen Marie Sofie Yoo1,O'Hanlon Karen A.1,Patzke Sebastian2,Holmberg Christian3,Mejlvang Jakob1,Groth Anja1,Nielsen Olaf3,Syljuåsen Randi G.2,Sørensen Claus Storgaard1

Affiliation:

1. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark

2. Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

3. Department of Biology, University of Copenhagen, Copenhagen, Denmark

Abstract

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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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