Molecular dynamics simulations on an Alliance cluster help biochemists understand how damaged DNA is recognized by a cell's genetic repair system.

Deep in the heart of every living cell, the DNA police are out in force. Patrolling precincts and checking IDs, they keep tabs on any suspicious movements, any deviant behaviors. One squad, known as the nucleotide excision repair system (NER), is so indispensable that no cell—whether from a bacterium or a blue whale—can go on for long without them.

The forte of NER is an uncanny ability to recognize friend from foe. From a dizzying range of healthy DNA sequences, it can recognize an impressive lineup of bad-apple mistakes, snip out the errors, and repair the chain good as new. At the same time, it doesn't step on the toes of other DNA repair systems, which fix other types of damage such as base mismatches. Keeping the message error-free is critical so that when the time comes for a cell to divide, it will pass on DNA free of potentially dangerous mutations.

An example of DNA damage recognized by the nucleotide excision repair system (NER.) At left is a normal DNA sequence. At right is the same sequence damaged by the carcinogenic HMT molecule (red). The damage has caused major changes to the conformation of the DNA, as seen in the distorted shape of the DNA backbone (green ribbons.) The damage has also affected interactions between nearby nucleotide bases (blue.) Together, these changes increase in the local flexibility of the DNA molecule, which in turn may make it recognizable by NER. Enlarge image.

In fact, bacteria and higher organisms have evolved two entirely different NER systems that can recognize and repair similar types of DNA damage. This suggests how important it is to keep an organism's genetic inheritance intact. But just how NER systems can find a few bad bases in a lengthy chain of sound DNA remains unknown.

Because these systems are so complex and poorly understood, two biochemistry researchers at the University of Kentucky are approaching the problem from the opposite direction. "What we're concerned with is, how does it recognize damage? And under what circumstances does the NER miss a problem?" says professor of biochemistry H. Peter Spielmann. Together with doctoral biochemistry student R. Jake Isaacs, Spielmann is working with Alliance supercomputers housed at the University of Kentucky to determine what it is about damaged DNA that makes it recognizable to NER systems.

Access Online | Posted 5-7-2002