Gardner, Richard

We're generally interested in how the cell regulates protein function through post-translational modifications. Such modifications are critical to the cell because, once a protein is made, the cell must be able to control the level of activity to balance it with need. Of the various known protein modifications, we're very interested in exploring how the small protein ubiquitin is used as a modifier of other proteins to alter their stability, enzymatic activity, interactions, localization, or other functions.

Ubiquitin was discovered as a covalent modifier of histone H2A nearly 30 years ago, and has since emerged as one of the cell's most broadly utilized protein modifications. From a systems perspective, ubiquitin can be thought of as a universal cellular rheostat, deployed in an array of different configurations that are used in distinct ways to regulate a myriad of activities. And though the full extent of ubiquitin's action in the cell is unknown, it's easy to imagine that every cellular process is controlled in some way by ubiquitination. The large number of genes encoding known or predicted ubiquitination-associated proteins in eukaryotic genomes - more than 900 in humans alone - hints at ubiquitin's vast regulatory potential. Functions for a considerable number of these ubiquitination-associated proteins have been identified in a variety of organisms. Most, however, remain functionally uncharacterized. Even for those with known functions, only a handful of substrates have been identified for each, but it's likely that they target many more substrates.

So, to expand our knowledge and approach a complete understanding of ubiquitin's scope within the cell, we're interested in discovering new ubiquitination pathways, especially those that function in the nucleus to regulate chromatin-associated processes or act in novel ways. To accomplish this, we're using classical genetic and biochemical techniques, as well as a variety of new high throughput methods, in yeast. Our ultimate goal is to discover new ubiquitination pathways in yeast, and then determine if analogous pathways similarly function in metazoans.