See a description of Deweese's research in his own words HERE.
Joseph Deweese, Ph.D., left, and Neil Osheroff, Ph.D., with a structural model of part of topoisomerase II, a protein that untangles DNA and is a target of anti-cancer and anti-bacterial drugs. (Photo by Susan Urmy, used by permission of the Vanderbilt Reporter)
In His Own Words
Published Research by Joe Deweese
My mentor, Dr. Neil Osheroff, and I were co-authors on this paper by Bryan Schmidt and Dr. James Berger (of UC Berkeley). Dr. Berger and Mr. Schmidt are X-ray crystallographers. Dr. Alex Burgin, another co-author, generated the DNA substrates used in the study.
The structure is of topoisomerase II covalently bound to DNA, which is the first structure of this enzyme/DNA complex. Topoisomerase II is essential to cells because of its role in unknotting DNA (especially DNA that is "linked" after DNA replication). Topoisomerase II cuts both strands of DNA and passes an intact DNA double helix through the broken strands. It then is able to reseal (or ligate) the broken DNA strands.
This enzyme is targeted by several anti-cancer and antibacterial drugs in order to kill cells. These drugs typically act by stabilizing the enzyme after it cuts DNA resulting in the accumulation of double strand breaks. These can overwhelm the cell and kill it.
While I was in graduate school in Dr. Osheroff's lab, I worked on DNA substrates that allowed us to trap topoisomerase II. In other words, topoisomerase II was able to cut DNA but not ligate (or reseal) DNA. We were able to establish reaction conditions to try to trap as much of the enzyme on the DNA substrates as possible so that Bryan could crystallize it and then generate a structure. Crystallization is very tricky, and Bryan was able to get a very good crystal that allowed him to generate the structure in the paper.
The structure gives us a better understanding of how the enzyme looks when it is attached to DNA. We are also able to learn about how it uses metal ions to cut the DNA since Bryan was able to get a structure with metal ions present (which again can be very tricky). This is of interest to me since the latter part of my graduate career was spent studying the use of metal ions during DNA scission by topoisomerase II.
Another interesting point is that his structure has two metal ions, which is consistent with findings from our laboratory published back in 2008 showing that the mechanism required two metal ions (Deweese, Burgin, Osheroff, Nucleic Acids Res. 2008 Sep;36(15):4883-93).