We study the regulation of the cell cycle in yeast cells (the kind that are used for baking bread and brewing beer). Even though yeast do not get cancer, they are a great system for research - they grow quickly and it is relatively easy to do lots of interesting experiments with them. Some of the things that we learn may be applicable to other eukaryotic organisms,, like people.

Proteins called cyclin-dependent kinases are strikingly conserved functionally and structurally among all eukaryotic organisms. These proteins are key positive regulators of the cell cycle. It may be helpful to think of them like the gas pedal in a car - the CDKs make the cell go through the cell cycle. Other proteins, like checkpoint proteins and CDK inhibitors, help cells stop the cell cycle if something bad (like damage to their DNA) occurs. Checkpoint proteins and CDK inhibitors are like the brakes in a car - they slow down or stop the cell cycle. Both types of genes can be mutated to cause unregulated cellular growth.

We have found that mutations in a checkpoint gene are lethal in combination with expression of some CDK subunits. To understand why the cells die, we isolated a suppressor of this lethality. We found that overexpression of RNR1 suppressed the mutation. RNR1 is a gene required for synthesis of deoxyribonucleotides (dNTPs; the subunits of DNA). Most likely, expression of the CDK subunit causes cells to accelerate their progress through the cell cycle. They begin to replicate their DNA before they have enough dNTPs to finish the job. Usually, the checkpoint pathway would slow them down. If the checkpoint pathway is mutated, the cells start to go through the cell cycle and die because they can't finish copying their DNA.

We have also isolated new mutations that are lethal in combination with a deletion of SIC1, a CDK inhibitor. These mutations may identify new checkpoint pathways.We have identified one gene and are in the process of understanding its role in the cell cycle and determining what proteins it interacts with. There are a few other mutants remaining to be characterized, and possibly cloned if we determine they have interesting phenotypes.