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FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe

Lucy Jennings1, Heather Andrews Walters1, Jennifer M Mason1

  • 1Department of Genetics and Biochemistry, Clemson University, Clemson University.

Biorxiv : the Preprint Server for Biology
|June 9, 2023
PubMed

Insights

Loss of the helicase FBH1 sensitizes cancer cells to WEE1 inhibition, increasing mitotic catastrophe. FBH1 deficiency impairs replication stress response but enhances WEE1 inhibitor efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • WEE1 kinase regulates cell cycle progression by phosphorylating CDK1/2, controlling origin firing and mitotic entry.
  • WEE1 inhibition is a promising cancer therapy strategy, inducing replication stress and G2/M checkpoint abrogation.
  • Understanding genetic factors influencing WEE1 inhibitor response is crucial for developing single-agent chemotherapeutics.

Approach:

  • Investigated the impact of FBH1 (helicase) loss on cellular response to WEE1 inhibition.
  • Assessed replication stress response, including ssDNA and double-strand break signaling, in FBH1-deficient cells treated with WEE1 inhibitors.
  • Quantified cell death, specifically mitotic catastrophe, in response to combined WEE1 inhibition and FBH1 deficiency.

Key Points:

  • FBH1 deficiency reduces replication stress signaling (ssDNA, double-strand breaks) upon WEE1 inhibition.
  • Despite impaired replication stress response, FBH1-deficient cells exhibit increased sensitivity to WEE1 inhibition.
  • This sensitization is characterized by a heightened induction of mitotic catastrophe.

Conclusions:

  • FBH1 is required for robust replication stress response signaling following WEE1 inhibition.
  • Loss of FBH1 sensitizes cells to WEE1 inhibition, primarily through increased mitotic catastrophe.
  • Replication-associated DNA damage in FBH1-deficient cells likely relies on the WEE1-dependent G2 checkpoint for repair.
Keywords:
DNA repairFBH1WEE1mitosisreplicationreplication catastrophe

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