Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest

• Published in: Molecular cell Vol. 71; no. 4; pp. 581 - 591.e5
• Main Authors: Reyes, José, Chen, Jia-Yun, Stewart-Ornstein, Jacob, Karhohs, Kyle W., Mock, Caroline S., Lahav, Galit
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.08.2018
• Subjects: Cell Cycle Checkpoints - genetics; Cell Cycle Checkpoints - radiation effects; Cell Division - radiation effects; Cell Line, Transformed; Cell Proliferation - radiation effects; cell-cycle arrest; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial Cells - radiation effects; Gamma Rays; Gene Expression Regulation; Genes, Reporter; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; heterogeneity; Humans; live-cell imaging; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Models, Statistical; p53; Protein Stability; Red Fluorescent Protein; Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - radiation effects; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; signaling dynamics; single cells; systems biology; Time-Lapse Imaging; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; systems biology; cell-cycle arrest; signaling dynamics; DNA damage; live-cell imaging; single cells; heterogeneity; p53
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.06.031

Biological signals need to be robust and filter small fluctuations yet maintain sensitivity to signals across a wide range of magnitudes. Here, we studied how fluctuations in DNA damage signaling relate to maintenance of long-term cell-cycle arrest. Using live-cell imaging, we quantified division profiles of individual human cells in the course of 1 week after irradiation. We found a subset of cells that initially establish cell-cycle arrest and then sporadically escape and divide. Using fluorescent reporters and mathematical modeling, we determined that fluctuations in the oscillatory pattern of the tumor suppressor p53 trigger a sharp switch between p21 and CDK2, leading to escape from arrest. Transient perturbation of p53 stability mimicked the noise in individual cells and was sufficient to trigger escape from arrest. Our results show that the self-reinforcing circuitry that mediates cell-cycle transitions can translate small fluctuations in p53 signaling into large phenotypic changes. [Display omitted] •Live single-cell profiling post-irradiation reveals heterogeneity in arrest maintenance•Heterogeneity in arrest maintenance results from noisy p53 pulse amplitude•The interplay between p21 and CDK2 translates p53 fluctuations into escape from arrest•High p21 levels are sufficient to establish arrest but insufficient to maintain it Reyes et al. show that individual human cells vary in their ability to maintain cell-cycle arrest in the course of 1 week after DNA damage. They show that fluctuations in the oscillatory dynamics of the tumor suppressor p53 can trigger a switch from an arrested to a proliferative state.