Daniel Finley graduated from Harvard College in 1980 and received his PhD from MIT in 1984, having worked with Alex Varshavsky and in collaboration with Aaron Ciechanover. His thesis work showed that the ubiquitin pathway is essential in mammals and is the major pathway for selective protein degradation. He was appointed in 1988 to the faculty at Harvard Medical School, where he remains today as a Professor in the Cell Biology Department. His laboratory is studying ubiquitination and proteasome function.
The lab’s main interest is the proteasome, the most intricate enzyme of the ubiquitin pathway and a key regulator of cellular function. Some time ago the group found that the proteasome, as it had been studied for decades, is missing a variety of key factors, since routine purifications strip them off. One is a deubiquitinating enzyme, Ubp6 (known in mammals as Usp14).
This is a powerful inhibitor of the proteasome. Ubp6 functions noncatalytically to delay the degradation of ubiquitinated substrate proteins. While it inhibits degradation, Ubp6 deubiquitinates the target protein. As deubiquitination proceeds (on a millisecond time scale), the loss of ubiquitin groups makes inhibition of degradation irreversible.
With Randy King, researchers from the lab identified small-molecule inhibitors of Usp14 from humans, which penetrate cells and allow for enhanced degradation of USP14 substrate proteins. Another proteasome-associated factor is Hul5, a ubiquitin ligase. Progressive deubiquitination of the substrate by Ubp6 is antagonized by Hul5. Thus, ubiquitin chains are in a dynamic state on the proteasome, and these chain dynamics regulate substrate selection by the proteasome.