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

Abstract

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 ( CDK 2) 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.

Hyperactive end joining repair mediates resistance to DNA damaging therapy in p53-deficient cells

“…RPE1 cells were dually labeled with PCNA-mCherry (to monitor cell cycle state transitions) and 53BP1-mVenus (to monitor DSB foci kinetics) (Fig. 2b) 23,24 . These dual labeled cells were treated with scrambled siRNA (si-Control) or siRNA targeting TP53 (si- TP53 ), the latter of which resulted in >90% knockdown of TP53 transcript and elimination of p53-dependent CDKN1A transcription in response to IR (Fig.…”

Eternal sunshine of the spotless cycle

“…(A) The human cell cycle consists of four phases: G1, S, G2, and M phase. Each phase duration is well fitted by an Erlang distribution with a characteristic rate (λ) and number of steps (k) (λ and k values are shown for RPE cells, from Chao et al, ). (B) The proposed model for uncoupling of cell cycle phase durations Top: In healthy cellular states, each cell cycle phase is regulated by a large number of factors, some of them heritable, that individually exert only a minor influence on the rate of cell cycle progression.…”

“…In a recent study, Chao et al () use quantitative measurements of cell cycle dynamics in human cells to propose a theoretical model whereby cell cycle progression in single cells is a succession of uncoupled, memoryless phases, each composed of a characteristic rate and number of steps.…”

“… Understanding the quantitative principles underlying the durations of each of the four cell cycle phases has remained a challenge, despite the extensive knowledge on the molecular components and mechanisms related to cell cycle control. In their recent study, Purvis and colleagues (Chao et al , ) quantify cell cycle phase durations in human cells and propose a model whereby cell cycle progression in single cells is a succession of uncoupled, memoryless phases, each composed of a characteristic rate and number of steps. …”

“… The quantitative principles underlying cell cycle phase durations have remained elusive. In their recent study, Purvis and colleagues (Chao et al , ) quantify cell cycle phase durations in single human cells and propose a model whereby cell cycle progression is a succession of uncoupled, memoryless phases.

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