Iowa State University Researcher Seeks to Understand DNA Repair
September 20th, 2012
AMES, Iowa -- An Iowa State University scientist is studying the process organisms use to repair DNA damage, opening up implications for human health and cancer research.
Everything that has DNA needs a way to repair it from a variety of assaults, such as from chemicals or radiation, said Scott Nelson said, an assistant professor in the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology. A single system, using two proteins or enzymes, has been identified as having a role in fixing damaged DNA.
"This enzyme complex is found in everything from viruses to plants to animals," he said. "It is relevant to human cancer because it's one of the complexes that cancer cells upregulate, or increase, to respond to treatment; so doctors want to inhibit that complex to increase the effectiveness of that treatment. But plants also respond to DNA damage caused by ultraviolet radiation by using these proteins to repair the DNA."
Nelson has received an $823,000 National Science Foundation grant to study the proteins, known as Mre11/Rad50, and their biochemical structure. He studies the complex using a virus that attacks bacteria, called a bacteriophage or phage, for short.
"It's sort of the lowliest of all organisms, if you can call it an organism, but people have been using phage as a model system for more than five decades," he said. "It's so simple, yet it carries all of its own enzymes to repair and replicate its DNA. That's why it's been a really good model system."
"My research comes down to understanding biology," he said. "This is an important protein complex for the biology of nearly every organism. It's surprising how little is known about it."
What is known is that it plays a vital role in repairing double strand breaks in DNA, which happen to both parts of DNA's double helix. After a break occurs, Mre11/Rad50 tries to repair it.
The repair results in three possible outcomes for the damaged cell: correct repair, cell death or incorrect repair. In incorrect repair, the genome is rearranged, rendering it unstable and possibly leading to a cancerous mutation, Nelson said.
After a mutation occurs, tumor cells may co-opt the cell's repair processes and escalate Mre11/Rad50 production, leading to increased DNA repair and spreading the cancer.
"I'm trying to understand the fundamental workings of this enzyme complex and with that knowledge people can do lots of different things; one of them might be to design inhibitors," he said.
Nelson is collaborating on similar projects with researchers at the Duke University Medical School and St. Jude Children's Research Hospital. The collaborator at St. Jude is trying to figure out the crystal structure of the complex to get an atom-level detail of what it looks like. The Duke collaborators take mutations Nelson's lab makes to the proteins to study how the mutations affect the function, relating that to how the proteins behave, and then examine the effect of these mutations on the organism and its ability to repair its DNA.
"The three of us are trying to link structure, biochemistry and the physiology in an organism, which is something that is not often done in a coordinated fashion," he said.
A recent finding from Nelson's lab was reported in the Journal of Biological Chemistry (Sept. 7 issue). Graduate student Dustin Albrecht and postdoctoral scholar Tim Herdendorf discovered a new aspect of Mre11/Rad50 complex regulation that involves a repetitive switching between different structures while it performs its DNA repair function.