Results from my research in John Tainer's laboratory completed in collaboration with Steve Yannone, Berkeley lab, include defining the structure and molecular mechanism of the WRN-exonuclease domain (WRN-exo). We find that WRN-exo belongs to the DnaQ family of proteins and our structures with metal ions that either support or inhibit catalytic activity reveal a two metal ion mediated mechanism of activity. We also observed that Ku70/80 stimulates the activity of the core WRN-exo domain but not of certain other related or unrelated exonucleases, impicating functions for WRN-exo in Ku70/80 pathways, such as double-strand break repair. Moreover, we observe an in vivo requirement for WRN-exo, where loss of activity results in an alteration of DNA end joining processes in human cells.

Oxidative stress has been implicated in many diseases, and the chief source of reactive oxygen within the cell is from the mitochondrion. Manganese superoxide dismutase (MnSOD) is the cell's primary defense against these reactive oxygen species in the mitochondria and MnSOD defects may contribute to neurodegenerative diseases. These structural studies are a collaborative study with Prof. David Silverman, University of Florida to further understandy the mechanisms of catalysis, in particular the hydrogen bonding network at the active site.