The fission yeast Schizosaccharomyces pombe is an excellent model system in which to study the coordination of cell growth and cell differentiation. In the presence of nutrients, fission yeast cells grow and divide; in the absence of nutrients, they stop growing and undergo cell differentiation. The molecular mechanisms underlying this response are not fully understood. Here, we demonstrate that Tor2, a fission yeast member of the TOR protein kinase family, is central to controlling the switch between cell growth and cell differentiation in response to nutrient availability. Tor2 controls cell growth and ribosome biogenesis by regulating ribosomal protein gene expression. We have found that Tor2 has an additional function in repressing sexual differentiation. Tor2 overexpression strongly represses mating, meiosis and sporulation efficiency, whereas Tor2 inactivation has the opposite effect, leading to cell differentiation, regardless of the nutritional conditions. This newly revealed function of Tor2 appears to operate by interfering with the functions of the transcription factor Ste11 and the meiosis-promoting RNA-binding protein Mei2. Thus, our data reveal a unique regulatory function of the Tor pathway – ensuring that growth and cell differentiation become mutually exclusive and that the choice between them depends on environmental conditions.

Cell division at the end of mitosis and G₁is controlled by Cdh1/Hct1, an activator of the E3-ubiquitin ligase anaphase-promoting complex (APC) that promotes the ubiquitylation and degradation of mitotic cyclins and other substrates. Cdh1–APC is active in postmitotic neurons, where it regulates axonal growth and patterning in the developing brain. However, it remains unknown whether Cdh1–APC is involved in preventing cell-cycle progression in terminally differentiated neurons. To address this issue, we used the small hairpin RNA strategy to deplete Cdh1 in postmitotic neurons. We observed that Cdh1 silencing rapidly triggered apoptotic neuronal death. To investigate the underlying mechanism, we focused on cyclin B1, a major Cdh1–APC substrate. Our results demonstrate that Cdh1 is required to prevent the accumulation of cyclin B1 in terminally differentiated neurons. Moreover, by keeping cyclin B1 low, Cdh1 prevented these neurons from entering an aberrant S phase that led to apoptotic cell death. These results provide an explanation for the mechanism of cyclin B1 reactivation that occurs in the brain of patients suffering from neurodegenerative diseases, such as Alzheimer's disease.

The Rag family of GTPases has been implicated in TORC1 activation in Drosophila and in mammalian cells in response to amino acids. We have investigated the role of Rag GTPases, Gtr1 and Gtr2, in TORC1 regulation in Schizosaccharomyces pombe. Fission yeast Gtr1 and Gtr2 are non-essential proteins that enhance cell growth in the presence of amino acids in the medium. The function of Gtr1 and Gtr2 in nutrient signaling is further supported by the observation that even in rich medium the deletion of either gene results in the promotion of mating, meiosis and sporulation, consistent with the downregulation of TORC1. We show that Gtr1 and Gtr2 colocalize with TORC1 in vacuoles, where TORC1 is presumably activated. Epistasis analyses indicated that Gtr1/Gtr2 functions downstream of Vam6 and upstream of TORC1 in response to amino acid signals. Our data demonstrate the existence of an evolutionarily conserved pathway with Vam6-Gtr1/Gtr2 activating TORC1, which in turns stimulates cell growth and inhibits sexual differentiation.

Lsm1 forms part of a cytoplasmic protein complex, Lsm1‐7‐Pat1, involved in the degradation of mRNAs. Here, we show that Lsm1 has an important role in promoting genomic stability in Saccharomyces cerevisiae . Budding yeast cells lacking Lsm1 are defective in recovery from replication‐fork stalling and show DNA damage sensitivity. Here, we identify histone mRNAs as substrates of the Lsm1‐7‐Pat1 complex in yeast, and show that abnormally high amounts of histones accumulate in lsm1 Δ mutant cells. Importantly, we show that the excess of histones is responsible for the lsm1 Δ replication‐fork instability phenotype, since sensitivity of lsm1 Δ cells to drugs that stall replication forks is significantly suppressed by a reduction in histone gene dosage. Our results demonstrate that improper histone stoichiometry leads to genomic instability and highlight the importance of regulating histone mRNA decay in the tight control of histone levels in yeast.