Ubiquitin signaling and cell cycle control

Human cells contain thousands of different proteins that control their function. The abundance of each protein is determined, in part, by its destruction. The ubiquitin system is the major regulator of protein destruction in human cells, and is essential for normal cell proliferation. Dysfunction in the ubiquitin system contributes to human diseases, including neurological disorders and cancer. Our goal is to determine how ubiquitin promotes normal cell cycle progression and how dysfunction contributes to disease.

cell cycle control by ubiquitin ligases

The cell cycle is the process which our cells go through to proliferate. As cells progress through each cell cycle stage, hundreds of proteins are made and destroyed. Substrates are selected for degradation by E3 ubiquitin ligases, of which there are more than 600 in humans. We are focused on determining the identity of E3 ligases involved in cell cycle progression, their mechanisms or action, and their cognate substrates. Are are particularly interested in two families of E3s, termed the APC/C and SCF, for which we have identified new substrates and mechanisms of action. This work is supported by grants from of the National Institute of Health and the American Cancer Society.

cell cycle control by deubiquitinases 

Like other post-translational modifications, ubiquitin is reversible. Thus, countervailing forces ultimately determine if and when a substrate is ubiquitinated and degraded. Ubiquitin is removed from substrates by catalytic proteases termed deubiquitinases or DUBs. There are nearly 100 unique DUBs in humans. DUBs play a critical role in cell cycle and genome integrity and represent an emerging class of therapeutic targets. We are studying which DUBs contribute to cell cycle, their targets, and how are they regulated. This work is supported by a grant from of the National Institute of Health.

global analysis of ubiquitin signaling networks 

A major challenge in the ubiquitin field is connecting enzymes with their substrates. This is particularly challenging because E3-substrate interactions are both fleeting and highly regulated. These interactions also only occur when the substrate is being destroyed. We have adopted various systematic approaches to connect enzymes with their targets. We previously leveraged large scale, genomic and proteomics methods that together mapped hundreds of substrates for the cullin family, the largest E3 family in humans. More recently, we combined orthogonal features among known substrates to predict targets for the APC/C, revealing its role in chromatin regulation. We similarly leveraged genetic screens performed in yeasts and humans to identify new substrates for the SCF. Our goal is to systematically map targets for E3s and DUBs, which remains a significant technological challenge using conventional approaches.