A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 10; pp. 2532 - 2537
• Main Authors: Heldt, Frank S., Barr, Alexis R., Cooper, Sam, Bakal, Chris, Novák, Béla
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.03.2018
• Subjects: Biological Sciences; Bistability; Cancer; Cell cycle; Cell Cycle - genetics; Cell Cycle - physiology; Cell proliferation; Cell Proliferation - genetics; Cell Proliferation - physiology; Cells; Cells, Cultured; Control systems; Control theory; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Damage; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA Damage - physiology; Enzyme inhibitors; External stimuli; Feedback loops; Gene Knockout Techniques; Humans; Kinases; Mathematical models; Mitogens - genetics; Mitogens - metabolism; Models, Biological; Mutation; Positive feedback; Robustness (mathematics); S phase; Single-Cell Analysis; Switches; proliferation–quiescence decision; mathematical modelling; cell cycle; DNA damage; live-cell imaging
• DOI: 10.1073/pnas.1715345115
• ISSN: 0027-8424; 1091-6490

Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation–quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.