Control of cell cycle commitment by APC-C-Cdh1

Division Of Basic Sciences - Nci

Investigators

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Abstract

The overall goal of this project is to investigate how stress and mitogen signaling pathways regulate the cell's decision to either enter or exit the cell cycle and to investigate the source of single-cell variability in this fate choice. It has been proposed that the decision to enter the cell cycle is made at a discreet point during G1 phase called the restriction point. However, we have shown that if cells encounter genotoxic stress even after they have passed the restriction point, they can still exit the cell cycle and return to quiescence, indicating cells have not yet committed to the cell cycle at the restriction point (Nathans et al, Science Advances, 2021). These results call into question the concept that cells make the decision to divide at a single point in the cell cycle and also demonstrate that the DNA damage-regulated G1/S checkpoint is highly ineffective. In FY2023, we now show that cells never actually irreversibly commit to the cell cycle. Using time-lapse imaging, single-cell tracking, and fluorescent biosensors, we show that the cell cycle remains fully reversible at any point if mitogen signaling is blocked (Cornwell et al, Nature, 2023). This finding has major implications for our basic knowledge of how the cell cycle works as well for how cancer cells may be targeted in patients. Future studies with this project will further investigate the implications of this new understanding of cell cycle commitment. Also in FY2023, we have made an important advance in building new tools for studying the cell cycle. We engineered a new biosensor to study the cell cycle-regulated ubiquitin ligase SCFbeta-TRCP. This ubiquitin ligase is often overexpressed in cancer cells and plays an important role in regulating stress signaling and inflammation, but little is known about how this ubiquitin ligase is regulated. We engineered a synthetic peptide that is degraded by SCF beta-TrCP and used this tool to both study beta-TrCP biology as well as use it as a screening tool to identify small molecule inhibitors of SCF beta-TrCP (Paul et al. Nature Commmunications, 2022).