Evidence that the human cell cycle is a series of uncoupled, memoryless phases

• Published in: Molecular systems biology 2019-03, Vol.15 (3), p.e8604-n/a
• Main Authors: Chao, Hui Xiao, Fakhreddin, Randy I, Shimerov, Hristo K, Kedziora, Katarzyna M, Kumar, Rashmi J, Perez, Joanna, Limas, Juanita C, Grant, Gavin D, Cook, Jeanette Gowen, Gupta, Gaorav P, Purvis, Jeremy E
• Format: Article
• Language: English
• Subjects: Cell cycle; Cell Cycle - physiology; cell‐to‐cell variability; computational systems biology; Coupling (molecular); Cyclin D; Cyclin D - genetics; Cyclin D - metabolism; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA Replication - genetics; EMBO06; EMBO33; Erlang model; Humans; Kinases; Model testing; Oncogenes - genetics; Phases; Probability distribution functions; single‐cell dynamics; Stem cells; Temperature
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20188604

The cell cycle is canonically described as a series of four consecutive phases: G1, S, G2, and M. In single cells, the duration of each phase varies, but the quantitative laws that govern phase durations are not well understood. Using time‐lapse microscopy, we found that each phase duration follows an Erlang distribution and is statistically independent from other phases. We challenged this observation by perturbing phase durations through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Despite large changes in durations in cell populations, phase durations remained uncoupled in individual cells. These results suggested that the independence of phase durations may arise from a large number of molecular factors that each exerts a minor influence on the rate of cell cycle progression. We tested this model by experimentally forcing phase coupling through inhibition of cyclin‐dependent kinase 2 (CDK2) or overexpression of cyclin D. Our work provides an explanation for the historical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states. Synopsis Time‐lapse imaging of cell‐cycle phase transitions reveals that phase durations are uncoupled and can be modeled as an Erlang process. Phase coupling can be forced by perturbing a strong cell‐cycle regulator acting on multiple phases. Cell‐cycle phase durations are uncoupled in three human cell lines. Each cell‐cycle phase proceeds like a sequence of memoryless steps that can be modeled as an Erlang process. A “many‐for‐all model”, in which large number of factors each exerting minor influence on phase duration, explains the stochastic but heritable nature of cell cycle progression. Coupling between cell‐cycle phases can be introduced by perturbing a cell‐cycle regulator of multiple phases. Graphical Abstract Time‐lapse imaging of cell‐cycle phase transitions reveals that phase durations are uncoupled and can be modeled as an Erlang process. Phase coupling can be forced by perturbing a strong cell‐cycle regulator acting on multiple phases. This article has been featured on the April cover of the journal.