Temporal phosphoproteomics reveals WEE1-dependent control of 53BP1 pathway
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Wee1-like protein kinase (WEE1) restrains activities of cyclin-dependent kinases (CDKs) in S and G2 phase. Inhibition of WEE1 evokes drastic increase in CDK activity, which perturbs replication dynamics and compromises cell cycle checkpoints. Notably, WEE1 inhibitors such as adavosertib are tested in cancer treatment trials; however, WEE1-regulated phosphoproteomes and their dynamics have not been systematically investigated. In this study, we identified acute time-resolved alterations in the cellular phosphoproteome following WEE1 inhibition with adavosertib. These treatments acutely elevated CDK activities with distinct phosphorylation dynamics revealing more than 600 potential uncharacterized CDK sites. Moreover, we identified a major role for WEE1 in controlling CDK-dependent phosphorylation of multiple clustered sites in the key DNA repair factors MDC1, 53BP1, and RIF1. Functional analysis revealed that WEE1 fine-tunes CDK activities to permit recruitment of 53BP1 to chromatin. Thus, our findings uncover WEE1-controlled targets and pathways with translational potential for the clinical application of WEE1 inhibitors.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 105806 |
| Tidsskrift | iScience |
| Vol/bind | 26 |
| Udgave nummer | 1 |
| Antal sider | 24 |
| ISSN | 2589-0042 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank the DTU proteomics platform that carried out the mass spectrometry measurements of the samples. This work was supported by Lundbeckfonden (Grant number R249-2017-1448 ) and Danish Cancer Society (Grant number R325-A18910 ). We would also like to thank Krister Wennerberg ( krister.wennerberg@bric.ku.dk ) and Daria Bulanova ( daria.bulanova@bric.ku.dk ) for providing the OVCAR3 and OVCAR8 cell lines.
Funding Information:
We thank the DTU proteomics platform that carried out the mass spectrometry measurements of the samples. This work was supported by Lundbeckfonden (Grant number R249-2017-1448) and Danish Cancer Society (Grant number R325-A18910). We would also like to thank Krister Wennerberg (krister.wennerberg@bric.ku.dk) and Daria Bulanova (daria.bulanova@bric.ku.dk) for providing the OVCAR3 and OVCAR8 cell lines. Conceived the project C.S.S. J.B. and V.P.; performed the research and analyzed the data V.P. and J.B.; assisted with mass spectrometry analysis E.M.S.; wrote the original manuscript V.P. J.B. and C.S.S.; provided comments to the manuscript and experiment design E.M.S. and O.N. The authors declare no competing interests.
Publisher Copyright:
© 2022 The Author(s)
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