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

Halfdan Beck | Zendy; Viola Nähse | Zendy; Marie Sofie Yoo Larsen | Zendy; Karen O’Hanlon | Zendy; Sebastian Patzke | Zendy; Christian Holmberg | Zendy; Jakob Mejlvang | Zendy; Anja Groth | Zendy; Olaf Nielsen | Zendy; Randi G. Syljuåsen | Zendy; Claus Storgaard Sørensen | Zendy

Open Access

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

Author(s) -

Halfdan Beck,

Viola Nähse,

Marie Sofie Yoo Larsen,

Karen O’Hanlon,

Sebastian Patzke,

Christian Holmberg,

Jakob Mejlvang,

Anja Groth,

Olaf Nielsen,

Randi G. Syljuåsen,

Claus Storgaard Sørensen

Publication year - 2012

Publication title -

molecular and cellular biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.14

H-Index - 327

eISSN - 1067-8824

pISSN - 0270-7306

DOI - 10.1128/mcb.00412-12

Subject(s) - biology , wee1 , dna replication factor cdt1 , licensing factor , g2 m dna damage checkpoint , microbiology and biotechnology , cyclin dependent kinase , origin recognition complex , replication factor c , control of chromosome duplication , dna replication , chek1 , dna re replication , genetics , eukaryotic dna replication , cell cycle , cell cycle checkpoint , cyclin dependent kinase 1 , dna , gene

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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