Important biosynthetic processes are separated in time

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Textbooks will tell you that in dividing cells, production of new DNA peaks during S phase, while production of other macromolecules such as proteins, lipids, and polysaccharides continues at more or less the same level. Molecular biologists at the University of Groningen, led by Professor Matthias Heinemann, have now discovered that this is not true: protein synthesis shows two peaks, lipid synthesis one peak. These shifts could explain the metabolic oscillations that lead to cell division that the group previously discovered. Their new results were published in natural metabolism on February 27th.

Every dividing eukaryotic cell goes through the cell cycle: from a growth phase (G1), through a phase of synthesis of new DNA (S), a gap phase (G2), and finally a phase of cell division by mitosis (M). Scientific texts on cell division show that apart from DNA synthesis, all other molecules in the cell, such as proteins, lipids and polysaccharides, are produced at a more or less constant rate during all phases of the cell cycle.

Dynamic measurements

Seven years ago, Matthias Heinemann and his group described oscillations in cell metabolism that apparently orchestrate the process of eukaryotic cell division. His team has now examined the metabolism more closely and measured the rate at which proteins, lipids and polysaccharides are produced during the cell cycle. And they discovered that the textbooks are wrong.

“We used dynamic microscopic measurements on individual cells to show how the production of different macromolecules peaks at different times,” explains Heinemann. The basal rate of protein synthesis peaked during G1 phase, slowed in S phase, and peaked again in the second half of the cell cycle. “We also found that the synthesis of both lipids and polysaccharides, the building blocks for the cell wall, peaks only once: also in the second half.”

building blocks

To determine the rate of protein synthesis, the scientists used an established method for monitoring fluorescent proteins. They also developed a second, more sophisticated method that allowed them to validate that protein production appeared to follow the two-wave pattern. “We had to develop this second method because our results contradicted what we and everyone else knew about cell cycle metabolism,” says Vakil Takhaveev, the first author of the paper. “With this novel method, we examined how sensitive a cell reacts to an inhibitor of protein biosynthesis at every moment of the cell cycle. It turns out that this sensitivity peaks at different phases of the cell cycle.”

In your natural metabolism Paper shows Heinemann and his team that the different building blocks for cells are not at the same time. The researchers also showed that the entire central metabolism has to adapt in order to satisfy this temporally separate production of building blocks. For example, they found that the speed of glucose consumption, ethanol excretion and respiration are associated with specific phases of the cell cycle.

Interestingly, these new measurements agree with their earlier findings, explains Heinemann: “The cell has to activate different biosynthetic pathways in order to produce amino acids or lipids. However, this leaves the question of how exactly this happens and why. “At the moment we can only speculate,” says Heinemann. “One aspect is that when a cell is simply growing, all of the building blocks are needed at the same time. However, when it comes to division, the situation is more complex. It could well be that the process of production can help the cell to divide.”

cancer and old age

Osmotic pressure might be the key. “Remember to inflate a balloon. In the beginning you need really high pressure, but once it starts to expand, a lower pressure will do. Perhaps the cell first produces many proteins to increase the osmotic pressure in the cell, which could help in the splitting off of the daughter cell,” says Heinemann. “Again, this is only speculation, but I believe that there is a biophysical reason behind the patterns we have observed.”

He will pursue these ideas further and search for the mechanisms that are responsible for the different phases of the synthesis of cell building blocks. “We don’t yet know how this works, but it would be extremely interesting to find out and see how these regulatory systems could be disrupted.” The current findings and future work are necessary for the basic understanding of cell physiology and will eventually help us fight cancer and aging.

Reference: Takhaveev V, Özsezen S, Smith EN, et al. The temporal segregation of biosynthetic processes is responsible for metabolic oscillations during the cell cycle of the budding yeast. Nat Metab. 2023;5(2):294-313. doi: 10.1038/s42255-023-00741-x


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