Toward a revised model of the cell cycle that captures reversible and irreversible arrest

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This research project will extend our knowledge of how cells undergo arrest, a state in which they are still alive but stop dividing—either temporarily or permanently. The textbook model of the cell cycle describes a single state of arrest but is mostly silent on whether this state consists of multiple arrested states; how cells may enter or exit these states; and how cells transition from reversible to irreversible arrest. This project will define the molecular steps that govern reversible and irreversible arrest and reveal how flexible the cell cycle is. These research objectives are deeply integrated with two community outreach activities that will engage a diverse group of students and scientists. Building on a long-term partnership with Durham public schools, seventh-grade students will learn the fundamentals of the cell cycle as well as the technical skills needed to perform microscopy. The project also draws on an existing partnership with the University of North Carolina's 'Treatment and Education of Autistic and Related Communication Handicapped Children' Program to employ two neurodiverse individuals to perform image analysis of cell cycle data.The first aim of this project focuses on reversible cell cycle arrest with the specific goal of determining how cells resume G1 and enter S phase following quiescence, a temporary state of cell cycle arrest. Perturbation experiments will test mechanisms by which the accumulation of CDKs/cyclins overwhelms pro-arrest factors to promote cell cycle re-entry. The second aim investigates mechanisms controlling irreversible cell cycle arrest, a phenotype commonly associated with cellular senescence. Time-lapse imaging and computational modeling will identify the precise sequence of molecular steps governing transition to permanent arrest. Systematic perturbation of G1 and G2 regulators are expected to relax the permanency of arrest. Successful completion of these research objectives will fill critical knowledge gaps in how the cell cycle is organized and regulated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.