FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe

• Published in: DNA repair Vol. 133; p. 103611
• Main Authors: Jennings, Lucy, Walters, Heather Andrews, McCraw, Tyler J, Turner, Joshua L, Mason, Jennifer M
• Format: Journal Article
• Language: English
• Published: Netherlands 01-01-2024
• Subjects: Cell Cycle Proteins - metabolism; Cell Death; Cell Line, Tumor; DNA Helicases - metabolism; Mitosis; Signal Transduction; Replication; WEE1; FBH1; Mitosis; DNA repair; Replication catastrophe
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2023.103611

WEE1 kinase phosphorylates CDK1 and CDK2 to regulate origin firing and mitotic entry. Inhibition of WEE1 has become an attractive target for cancer therapy due to the simultaneous induction of replication stress and inhibition of the G2/M checkpoint. WEE1 inhibition in cancer cells with high levels of replication stress results in induction of replication catastrophe and mitotic catastrophe. To increase potential as a single agent chemotherapeutic, a better understanding of genetic alterations that impact cellular responses to WEE1 inhibition is warranted. Here, we investigate the impact of loss of the helicase, FBH1, on the cellular response to WEE1 inhibition. FBH1-deficient cells have a reduction in ssDNA and double strand break signaling indicating FBH1 is required for induction of replication stress response in cells treated with WEE1 inhibitors. Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.