2024-02-12 10:36:51
In cell divisions, whether mitosis or meiosis, two key stages exist: the replication of DNA during a phase called S phase and the separation of chromosomes during M phase. The speed and coordination of these two phases is controlled by molecular modifications called phosphorylation. These modifications involve the addition of a phosphorylated group by enzymes called kinases, or the removal of this same group by enzymes called phosphatases. These enzymatic actions alter the activity of the proteins involved, thus playing a crucial role in the precise control of cellular events during division.
Yeast, the paragon of our knowledge of cell divisions
Meiotic division (meiosis) is specific to reproductive cells, the gametes, and aims to form different cells, thus contributing to the genetic diversity of species. Meiosis is a division whose originality is based on the sequence of two M-phases of division, called meiosis I (MI) and meiosis II (MII), in the absence of an intermediate S-phase. This has the effect of reducing its number of chromosomes by half and producing haploid cells (cells that have only one set of chromosomes).
In order to accomplish this cellular feat, the phosphoproteome, which brings together all the proteins that can be modified by kinases and phosphatases, must be modified between the two M-phases. The objective is to achieve in fine to successful chromosome segregation and avoid any errors that would be deleterious to the survival of the cell, or the embryo, in more evolved organisms. In this area of research, yeast has been used extensively to study cell divisions. We owe him numerous discoveries, particularly on enzymes called kinases and phosphatases, whose activities determine whether a given protein is phosphorylated or dephosphorylated during the cell cycle. Kinases not only incorporate phosphates into proteins but must also position them in the right place and at the right time in the cycle to ensure its smooth progress, i.e DNA replication first and then its division. The best known of these kinases is Cyclin-Cdk which orchestrates cell cycle progression. It phosphorylates key proteins in DNA replication or cell division and regulates the activity of other kinases and phosphatases controlling the cycle.
Understanding meiotic division by comparing its first division to that of mitosis
In this study, the scientists sought to determine how exit from meiosis I (which is followed by a second MII phase) differs from exit from mitosis (which is followed by an S phase). Using the budding yeast model, S. cerevisiae, the researchers analyzed changes in the phosphoproteome between the two meiotic M-phases in a time-resolved manner. This approach made it possible to follow the kinetics of thousands of phosphorylation events on cell cycle proteins at the end of meiosis I in a normal context and after an artificial reduction of Cdk activity. They then compared the results obtained with previous data generated on mitotic exit in order to decipher the molecular particularities specific to meiotic division.
In mitosis, the exit from division is characterized by a very significant dephosphorylation of the sites targeted by Cdk in order to reset the cell cycle and initiate an S-phase. At the end of meiosis I, on the other hand, scientists have shown that the phosphorylations on Cdk sites are very stable. The vast majority of substrates phosphorylated by Cdk are therefore not reset, suggesting that Cdk sites must remain phosphorylated to ensure the succession of two M-phases in meiosis. However, many proteins are still dephosphorylated, but at sites not recognized by Cdk. These results suggest that Cdk is not the only critical player in meiosis I exit and that other kinases and phosphatases are essential to control the succession of the two meiotic divisions.
Meiosis: the Cdk kinase influences the succession of the two division phases
The scientists then reconstituted at the exit of meiosis I a state similar to that of an exit from mitosis, by strongly reducing the specific activity of Cdk. Surprisingly, the complete drop in Cdk activity recreates the classical patterns of phosphorylation observed in mitosis for Cdk sites and the other kinases it regulates. This result demonstrates that maintaining a threshold of Cdk activity at the end of meiosis I is necessary to avoid the sequential dephosphorylation of proteins and therefore the complete reset of the cell cycle at the end of meiosis I. They thus demonstrate that meiotic cells have the plasticity necessary to partially reproduce the mitotic scenario. This experiment also revealed phosphorylation behaviors specific to meiotic division. Indeed, certain phosphorylations do not follow a mitotic profile following the abrupt drop in Cdk activity, revealing that kinases specific to meiosis and above all not regulated by Cdk activity, control the succession of the two M phases.
These results will make it possible to target more precise studies on the proteins concerned in order to elucidate their specific functions in meiosis.
© Sandra Touati
Figure : A. During mitotic exit, Cdk substrates are dephosphorylated. Many substrates not recognized by Cdk are also recognized. B. At the end of meiosis I, Cdk substrates are stable and dephosphorylations mainly target substrates not recognized by Cdk. C. At the end of meiosis I, when Cdk activity is artificially reduced, the substrates recognized by Cdk are dephosphorylated as in mitosis. On the other hand, certain substrates resist this reduction and remain stable.
Learn more:
Celebic D, Polat I, Legros V, Chevreux G, Wassmann K, Touati SA*. Qualitative rather than quantitative phosphoregulation shapes the end of meiosis I in budding yeast, EMBO J, 6 February 2024.
1707735080
#Highlighting #molecular #modifications #specific #gametogenesis