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Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):23891-23893. doi: 10.1073/pnas.1915108116. Epub 2019 Nov 11.

WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells.

Author information

1
Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213; t.n.moiseeva@gmail.com.
2
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15260.
3
Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213.
4
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206.

Abstract

WEE1 kinase is a key regulator of the G2/M transition. The WEE1 kinase inhibitor AZD1775 (WEE1i) induces origin firing in replicating cells. We show that WEE1i induces CDK1-dependent RIF1 phosphorylation and CDK2- and CDC7-dependent activation of the replicative helicase. WEE1 suppresses CDK1 and CDK2 kinase activities to regulate the G1/S transition after the origin licensing is complete. We identify a role for WEE1 in cell cycle regulation and important effects of AZD1775, which is in clinical trials.

KEYWORDS:

CDK1; DNA replication; RIF1; WEE1; cell cycle

PMID:
31712441
DOI:
10.1073/pnas.1915108116
Free PMC Article

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