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How an insidious mutation fools DNA replication

DURHAM, N.C. -- Biochemists have pinpointed how a flaw in DNA that is central to mutations in cancer and aging fools the cellular enzyme that copies DNA. Their finding explains how oxidative DNA damage -- a process long believed to underlie cancers and aging -- can create permanent genetic damage.

The Duke University Medical Center researchers' findings were published online Aug. 22, 2004, by the journal Nature. The scientists were led by Associate Professor of Biochemistry Lorena Beese, Ph.D., and the paper's lead author was Gerald Hsu, a Duke M.D./Ph.D. student. The other co-authors are Thomas Carell and Matthias Ober of Ludwig Maximillians University in Germany. Their research was supported mainly by the National Cancer Institute.

DNA is a double stranded molecule shaped like a spiral staircase. The two strands of the spiral are linked by sequences of molecular subunits, or bases, called nucleotides. The four nucleotides -- guanine, cytosine, adenine and thymine -- naturally complement one another like puzzle pieces. In normal DNA, a guanine matches with a cytosine, and an adenine with a thymine. However, stray reactive oxidizing molecules in the cell can alter guanine to become an "8-oxoguanine" that can lead to a mismatch.

This mismatch occurs in the process of replicating DNA, which begins when the two strands unzip. A protein enzyme called DNA polymerase then works its way along one "template" strand adding nucleotides to create a new double-stranded DNA. In the replication process, the polymerase draws the DNA strand through a small "active site" -- somewhat like a spaghetti strand being drawn through a Cheerio.

Normally, this "high-fidelity" polymerase accurately adds complementary nucleotides and detects any mistakes that have been made. These mistakes or mismatches reveal themselves as malformations that distort the active site -- like kinks in the spaghetti strand that would clog the Cheerio. Such malformations trigger a r
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Contact: Dennis Meredith
dennis.meredith@duke.edu
919-681-8054
Duke University Medical Center
30-Aug-2004


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