Apr 5 2004
The National Cancer Institute has awarded USC scientists $3.5 million for a study of the enzyme that faithfully copies our genetic information, enabling it to pass from one generation to the next.
The grant will fund structural, biochemical and computer studies designed to reveal how the enzyme, DNA polymerase, makes so few mistakes.
"This is a unique opportunity to marry theory and experiment in molecular and computational chemical biology," said principal investigator Myron Goodman, professor of biological sciences and chemistry in the USC College of Letters, Arts and Sciences.
"We're asking questions that can't be asked without theoretical tools, and they can't be answered without experimental and structural work," said Arieh Warshel, professor of chemistry, who will lead the theoretical part of the project and guide the modeling of the enzyme's activity using sophisticated computer software he's developed.
When a cell divides, DNA polymerase copies the cell's DNA, using the sequence of DNA bases, the strong affinity between bases (A pairs with T; C with G), and, most importantly, the enzyme's exquisite catalytic selectivity, to add the correct base to the growing strand.
The enzyme adds the wrong, mismatched DNA base only once in every 10,000 to one million bases. Further proofreading drops the overall error rate to one in a billion-about six mistakes per cell division.
Most of these mutations are benign or neutral, but some may lead to cancer.
"The question is how the enzyme knows when it's got the correct DNA base versus the incorrect one, and how that changes the speed of the reaction," Warshel said.
A third project led by structural biologist Samuel Wilson, deputy director of the National Institute of Environmental Health Sciences, will provide detailed 3-D "snapshots" of the enzyme.
Based on the snapshots, Warshel's studies will lead to specific predictions, which Goodman's team will test in the lab and then provide feedback on the model. Once the model is perfected, all three groups will study altered versions of the enzyme to identify activities essential to its accuracy.