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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle / physiology
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / physiology*
  • G1 Phase / drug effects*
  • HEK293 Cells
  • Humans
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology*
  • Pyrazoles / pharmacology*
  • Pyrimidinones / pharmacology*
  • S Phase / drug effects*
  • Telomere-Binding Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Pyrazoles
  • Pyrimidinones
  • Rif1 protein, human
  • Telomere-Binding Proteins
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • adavosertib