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_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Beck H,Nähse-Kumpf V,Larsen MS,O'Hanlon KA,Patzke S,Holmberg C,Mejlvang J,Groth A,Nielsen O,Syljuåsen RG,Sørensen CSdoi
10.1128/MCB.00412-12subject
Has Abstractpub_date
2012-10-01 00:00:00pages
4226-36issue
20eissn
0270-7306issn
1098-5549pii
MCB.00412-12journal_volume
32pub_type
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