Amino Acid Starvation Control of Cell Cycle Progression
Cell cycle progression is controlled at multiple points by multiple mechanisms. Checkpoints exist that allow the cell to block cell cycle progression if certain cellular processes have not progressed sufficiently or if errors have occurred. We were interested in how cells respond to deprivation for amino acids and have found an interesting an unexpected effect that modulates progression from the G1 to the S phase of the cell cycle.
These experiments grew out of studies we were doing on transcriptional control of the Ty retrotransposons during amino acid deprivation. We found that starving a gcn4 mutant cell for arginine caused the cells to accumulate that were at the G1/S boundary. By selecting for high-copy plasmids that reversed this phenotype we found three genes that could suppress this effect. One of these genes is involved in arginine metabolism. A second is the gene encoding a TATA binding factor associated protein (a TAF). The third encodes a subunit of the proteasome, Pre2. The first two genes appear to be involved directly in arginine metabolism. Pre2 does not since its overexpression does not reverse arginine starvation, but simply allows starved cells to continue growing.
We have shown that overexpression of other proteasome subunits does not allow growth in the absence of arginine. Surprisingly, all of the proteasome subunits that we have tested are transcriptionally repressed by amino acid starvation. Pre2 plays a critical role of the Pre2 protein in proteasome assembly, regulating the joining of half-mer subunits into the mature 20S proteasome. Lack of this protein may have a much stronger effect on assembly of proteasomes that does the lack of other subunits.
What is interesting about this system is that the availability of new proteasome subunits appears to regulate transit through a critical step in the cell cycle. We are interested in how the morphogenesis of the proteasome is monitored to do this.