CDK1 inhibitor controls G2/M phase transition and reverses DNA damage sensitivity.

Abstract

CDK1 plays key roles in cell cycle progression through the G2/M phase transition and activation of homologous recombination (HR) DNA repair pathway. Accordingly, various CDK1 inhibitors have been developed for cancer therapy that induce prolonged G2 arrest and/or sensitize cells to DNA damaging agents in tumor cells, resulting in cell death. However, CDK1 inhibition can induce resistance to DNA damage in certain conditions. The mechanism of different DNA damage sensitivity is not completely understood. We performed immunofluorescence and flow cytometry analysis to investigate DNA damage responses in human tumor cells during low and high dose treatments with RO-3306, a selective CDK1 inhibitor. This comparative investigation demonstrated that RO-3306-induced G2 arrest prevented cells with DNA double-strand breaks from transitioning into the M-phase and that the cells maintained their DNA repair capacity in G2-phase, even under RO-3306 dose-dependent DNA repair inhibition. These findings reveal that CDK1 inhibitor-induced DNA repair inhibition and cell cycle control, which regulate each other during the G2/M phase transition determine the cellular sensitivity to DNA damage, providing insight useful for developing clinical strategies targeting CDK1 inhibition in tumor cells.

• Authors: Shigeaki Sunada, Hiroko Saito, Doudou Zhang, Zeyu Xu, Yoshio Miki
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 550 Pg. 56-61 (04 23 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 33684621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Quinolines
• RO 3306
• Thiazoles
• CDC2 Protein Kinase
• CDK1 protein, human

Topics

• CDC2 Protein Kinase (antagonists & inhibitors)
• Cell Division (drug effects)
• Cell Line, Tumor
• DNA Damage (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Protein Kinase Inhibitors (pharmacology)
• Quinolines (pharmacology)
• Recombinational DNA Repair (drug effects)
• Thiazoles (pharmacology)