Investigating Systems of DNA Repair
Though you might not like to think about it, every day thousands of cells in your bodyand the DNA within themare damaged by carcinogens you encounter, in everything from cigarette smoke to industrial pollutants. The vast majority of the time, specialized DNA repair systems come to the rescue, quickly repairing the damage and setting everything right. The role of these repair systems in the health of your cells is crucial: if enough damaged DNA slips through the system without being repaired over time, it can ultimately spell the onset of cancer.
Yet as vital as these repair systems are, exactly how they recognize the damaged DNA within a cell is not fully understood. Associate professor of molecular and cellular biochemistry Peter Spielmann is working on the nucleotide excision repair system (NER), and his research has shown how the cell's "universal fix it" is able to detect and repair DNA damage of all different shapes and sizes.
Once NER detects damage, it chemically excises the section of DNA containing the problem so that the cell's normal replication machinery can then fill in that damaged area using correct information on the DNA's complementary strand to make an error-free repair. Until now, scientists have tended to focus on the repair process itself, taking the damage-recognition step almost for granted. But for Spielmann, that initial recognition stage is a subtle, and compelling, scientific process.
"There's something intrinsic about causing damage to the DNA which allows it to be recognized by the system," Spielmann says. "So right now we're examining the structure of the damaged DNA molecules to try to understand what it is about the damage that signals to these enzymes that there is a problem."
Utilizing the university's supercomputer, Spielmann has calculated and compared the trajectoriesor patterns of movementof both damaged and undamaged DNA molecules. With over 10,000 hours of supercomputing computation, he was able to create a visual "movie" of the movements of DNA molecules over 10 nanoseconds. His results so far suggest that it is the heightened mobility of damaged DNA that alerts the NER to repair it. Spielmann has verified these computational results with experimental results using nuclear magnetic resonance spectroscopy.
"With current technology, we can analyze these DNA trajectories for things like subtle conformational features, as opposed to just saying 'it moves around a lot,'" Spielmann says.
His research on NER may eventually lead to drugs that could serve as short-term inhibitors of DNA repair, increasing the efficacy of chemotherapeuticsmany of which target DNA directly in order to damage and kill malignant cellsfor cancer patients.
About Peter Spielmann
In addition to DNA dynamics, Peter Spielmann is also interested in protein prenylationa metabolic event that allows molecules within a cell to interact with each otherand in analyzing the chemistry of new materials called fullerines. "Primarily, my main motivation is, how do atoms get on with each other. That's what I like to know about," says Spielmann, who came to UK in 1995.
Spielmann Research Team
Richard Isaacs, postdoc researcher, Vanderbilt University, and former UK biochemistry graduate student