Temporal phosphoproteomics reveals WEE1-dependent control of 53BP1 pathway

Valdemaras Petrosius, Jan Benada, Olaf Nielsen, Erwin M. Schoof, Claus Storgaard Sørensen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

4 Citations (Scopus)
18 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number105806
JournaliScience
Volume26
Issue number1
Number of pages24
ISSN2589-0042
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • Cancer
  • Molecular biology
  • Omics

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