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Nitrogen Availability and TOR Signaling Regulate Mitotic Fidelity in Fission Yeast


Core Concepts
Nitrogen availability and the TOR signaling network play a critical role in ensuring successful progression through mitosis and maintaining mitotic fidelity in fission yeast.
Abstract
The study investigates the role of nitrogen availability and the TOR signaling network in regulating mitotic fidelity in the fission yeast Schizosaccharomyces pombe. Key highlights: Supplementation of the growth medium with good nitrogen sources, such as ammonium or glutamate, can partially rescue the catastrophic mitotic phenotypes observed in various mutants, including those with perturbed lipid metabolism. The nitrogen-dependent rescue of mitotic defects is not achieved by restoring the aberrant lipid composition or nuclear envelope expansion in the mutants. Instead, it is mediated by the TOR signaling network, particularly the growth-promoting Tor2/TORC1 complex. Inhibition of the stress-responsive Tor1/TORC2 branch or activation of Tor2/TORC1 also improves mitotic fidelity, suggesting a novel role for the TOR network in regulating successful progression through mitosis. The nitrogen-dependent rescue effect is not limited to lipid metabolism mutants but can also be observed in a diverse panel of other "cut" mutants, indicating a more general role of nitrogen availability and TOR signaling in mitotic fidelity. The authors propose that the signaling of nitrogen availability, rather than the physical presence of nutrients, is the key factor in mediating the rescue, potentially by establishing conditions more favorable for smooth mitotic progression early in the cell cycle.
Stats
Δcbf11 cells have lower fatty acid content per unit of dry cell weight compared to WT. The degree of fatty acid saturation is higher in Δcbf11 cells compared to WT. The abundance of selected fatty acid species (C18:1, C18:0, C16:0) is altered in Δcbf11 cells compared to WT. The content of squalene and sterol esters is markedly increased in Δcbf11 cells compared to WT.
Quotes
"Ammonium, a prototypical good nitrogen source, had the most profound effect, suppressing mitotic defects even at reduced concentrations." "Glutamate, another good nitrogen source, could also improve mitotic fidelity, albeit only at higher concentration." "The poor nitrogen sources proline and uracil did not suppress the mitotic defects of Δcbf11 cells at the concentrations tested."

Deeper Inquiries

How might the nitrogen-dependent regulation of mitotic fidelity be conserved in higher eukaryotes that undergo open mitosis?

In higher eukaryotes that undergo open mitosis, the regulation of mitotic fidelity through nitrogen availability may still be conserved, albeit with some differences. While the specific mechanisms may vary, the fundamental principle of nutrient sensing and utilization impacting cell cycle progression is likely to be conserved. For example, in open mitosis, the availability of nitrogen sources could influence the timing of mitotic entry, progression through different mitotic phases, and the fidelity of chromosome segregation. The TOR signaling network, which plays a crucial role in nutrient sensing and cell cycle regulation, is conserved in higher eukaryotes and could mediate the effects of nitrogen availability on mitotic fidelity. Additionally, the impact of nitrogen availability on lipid metabolism, membrane dynamics, and chromatin structure, as observed in the study on fission yeast, could also have implications for mitotic fidelity in higher eukaryotes.

What are the specific downstream effectors and mechanisms by which the TOR signaling network regulates mitotic progression and ensures mitotic fidelity?

The TOR signaling network regulates mitotic progression and ensures mitotic fidelity through a variety of downstream effectors and mechanisms. In the context of the study on fission yeast, the TOR network, particularly the Tor2/TORC1 complex, plays a critical role in responding to nitrogen availability and coordinating cell cycle progression. Specific downstream effectors of the TOR network involved in mitotic regulation may include factors that control the timing of mitotic entry, progression through different mitotic phases, and the fidelity of chromosome segregation. These effectors could include proteins involved in spindle assembly, chromosome condensation, and cytokinesis. Additionally, the TOR network may influence the expression of genes related to cell cycle control, lipid metabolism, and membrane dynamics, all of which are essential for proper mitotic progression. The TOR network may also interact with other signaling pathways and regulatory networks to coordinate mitotic events and ensure accurate chromosome segregation.

Could the insights from this study on the role of nitrogen availability and TOR signaling in mitotic regulation be leveraged to develop novel therapeutic approaches for diseases associated with mitotic defects, such as cancer?

The insights from this study on the role of nitrogen availability and TOR signaling in mitotic regulation could indeed be leveraged to develop novel therapeutic approaches for diseases associated with mitotic defects, including cancer. Understanding how nutrient availability and signaling pathways impact mitotic fidelity can provide valuable insights into the mechanisms underlying abnormal cell division in cancer cells. Targeting the TOR signaling network, which is often dysregulated in cancer, could be a potential strategy to modulate mitotic progression and improve the fidelity of chromosome segregation in cancer cells. By manipulating nutrient availability or targeting specific downstream effectors of the TOR network involved in mitotic regulation, novel therapeutic interventions could be developed to enhance the efficacy of existing cancer treatments or to overcome drug resistance mechanisms. Additionally, the findings from this study may inspire further research into the intersection of metabolism, cell cycle control, and mitotic fidelity in the context of cancer biology, leading to the development of innovative therapeutic strategies targeting mitotic defects in cancer cells.
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