Identification of an essential checkpoint for a smooth cellular function
Illustration: diagram of the negative correlation between the cell size and the duration of phase G1
Aug. 16, 2018
Coordinating cell growth and division is essential to their functioning. In baker's yeast, the mechanism by which cell size control is achieved during cell cycle is still largely unknown. In this study, Gilles Charvin's team at the IGBMC (CNRS/Inserm/University of Strasbourg) identified a new cell size checkpoint during the cell cycle. These results are published on August 9th in the journal eLife.
Cellular proliferation can be viewed as the sum of two processes – growth and division – that require appropriate coordination. A cell size checkpoint has long been reported during the G1 phase of the cell cycle in baker’s yeast: when the cell is too small, this G1 phase checkpoint blocks its entry into the cell division phase until it has reached the required size. The duration of the G1 phase is therefore longer the smaller the cell size at birth. Several models have been proposed to explain how size sensing is operated at the molecular level, yet the detailed mechanism is still obscure.
In this study, researchers from Charvin's team wondered if such a checkpoint could exist in other phases of the cell cycle. To test this hypothesis, they used a fluorescent marker to break down the cycle into its four phases and correlate cell size with the duration of each phase. More precisely, this marker allowed them to observe the synthesis of histones, proteins associated with DNA whose quantity fluctuates during cell cycle progression.
First, the researchers validated their technique by observing the cell size control that takes place in G1 phase of the cell cycle. Then, they not only identified another checkpoint in G2 phase but also demonstrated that the strength of this control point was larger than that of G1.
To confirm their observations, the researchers observed the impact of mutations of cell cycle genes on this mechanism. They have thus shown that mutants involved in the progression of the G1 phase have little effect on cell-to-cell variability. Instead, among the cell cycle genes tested that affect size progression in G2, the researchers found that genes related to the regulation of cyclin B-Cdk activity had the strongest impact on cell-to-cell size variability.
This study, in which cell cycle progression was followed with unprecedented precision in yeast, demonstrates that cell-to-cell variability does not come from a specific mechanism, but is the result of multiple inputs that coordinate cell growth with division.
This study was supported by the ATIP-Avenir (G.C.) program, the Fondation pour la Recherche Médicale (G.C.), and the ANR.