Pharmacy professor's protein research published in the journal <em>Nature</em>

Janel Shoun | 

 

Lipscomb University Assistant Professor of Pharmaceutical Sciences Joe Deweese, Ph.D., has been published by the journal Nature, the weekly, interdisciplinary journal of science.
 
An abstract of the Nature article is available HERE.
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)
Nature is an international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions.
 
Nature is the world's most highly cited interdisciplinary science journal, according to the 2008 Journal Citation Report Science Edition.
 
Deweese, along with Neil Osheroff, Ph.D., of Vanderbilt University, was a co-author of, “A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases,” a paper published in the Nature  on June 3 (465:641-644). The paper outlines a method of crystallizing a specific protein in complex with DNA, allowing scientists to study the DNA/protein complex from a structural standpoint.
 
Additional study of this protein will add to the knowledge needed to better target anti-cancer drugs and therapies, said Deweese, who also serves as an adjunct assistant professor in biochemistry at Vanderbilt University.
 
Deweese has also been published in academic journals such as Biochemistry, Nucleic Acids Research, and Biochemistry and Molecular Biology Education.
 
Deweese came to the Lipscomb College of Pharmacy in June 2009. He also works with the College of Pharmacy’s Pharmaceutical Sciences Summer Research Program, allowing students to work in research labs during the summer in collaboration with faculty members in the College of Pharmacy’s Department of Pharmaceutical Sciences at Lipscomb University and the Departments of Pharmacology and Biochemistry at Vanderbilt University.
 
“The type of collaborative research Dr. Deweese is involved in on a daily basis is critical as we create innovative research and training opportunities for our students and faculty at local research institutions, biotech companies and academic health centers,” said Scott Akers, chair of the Department of Pharmaceutical Sciences in the College of Pharmacy.   “It also opens the door for student pharmacists interested in pursuing a research careerto gain access to some of the premier graduate and scientific programs in the world.”
 
The College of Pharmacy, established in 2006, is committed to providing opportunities for student pharmacists to not only enter practice careers, but to advance into research careers and doctorate-level studies.
 
Click Here to see the Vanderbilt Reporter story on Deweese and Osheroff.
 
 
 
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).