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Scientists Discover Evolutionary Adaptation to DNA Repair in Human Cells

La Jolla, CA. January 26, 2000 -- Researchers at The Scripps Research Institute (TSRI) studying a key human DNA repair enzyme have discovered an evolutionary adaptation that highlights a fundamental advantage in the way human cells repair damage to their DNA. Together with their colleagues at the Sealy Center for Molecular Science at the University of Texas Medical Branch (UTMB) in Galveston, they have demonstrated that a key DNA repair enzyme is optimized to remain bound to its toxic, damaged DNA products until the next enzyme in the DNA repair pathway can take over. This adaptation allows for DNA repair in human cells to be coordinated between subsequent enzymes in the pathway, rather than having harmful DNA damage intermediates exposed in the cell.

According to Clifford D. Mol, Ph.D., Senior Research Associate, Department of Molecular Biology at TSRI and lead author of the report, "This has important implications, for example, in cancer chemotherapy regimes in that it may be possible to overwhelm DNA repair processes when the amount of DNA damage is very high."

The study, "DNA-Bound Structure and Mutants Reveal A Basic DNA Binding by APE1 Coordinates DNA Repair," appears in Nature magazine on January 27, 2000.

DNA is damaged continuously in all cells, both as a result of normal metabolism and ionizing radiation. Critical DNA base excision repair (BER) enzymes find these damaged bases that can cause mutations leading to cancer and other diseases and remove them from DNA. The product of these enzymes is an abasic nucleotide or "hole" in the DNA helix, called an abasic or apurinic/apyrimidinic (AP) site. These sites must be repaired to restore the DNA sequence prior to DNA replication. They are processed by AP endonucleases, which detect the sites and initiate the replacement of the damaged base with an undamaged one.

TSRI scientists and their UTMB colleagues determined the three-dimensional structure of the human AP endonuclease enzyme bound to its damaged AP-site, as well as the structure of the enzyme bound to a cleaved DNA product. Mol explained, "AP sites in human DNA repair are processed by an enzyme called AP endonuclease-1, or APE1. When we looked closely at the structures it became clear that APE1 did not work the way everyone thought it did. Actually seeing the bond being cleaved really helps clarify the reaction mechanism. (To view the animation, visit Including a scientific animation of the new structure-based reaction mechanism helps to make the results more understandable and accessible to non-specialists and the general public."

More surprising results were obtained in the laboratory of Sankar Mitra, Ph.D., at UTMB, where Tadahide Izumi, Ph.D., tested whether the APE1 residues that penetrate the DNA grooves are needed to flip the AP site out of the helix. None of the inserting residues were required for APE1 activity and one of the mutants was actually a more efficient enzyme than the original, suggesting that the normal APE1 enzyme is optimized to remain bound to its reaction products.

"Perhaps the most important implication of this work is that a critical DNA repair enzyme is not optimized for a single chemical step but rather for an entire biological pathway," comments John A. Tainer, Ph.D., Professor, Department of Molecular Biology and The Skaggs Institute for Chemical Biology. "The emerging view from this work is the individual chemical steps controlling genetic integrity are integrated like a dance where partner exchanges, steps and timing are carefully choreographed. This understanding has profound implications for evaluating human risk from environmental toxins and from the polymorphisms or variations being discovered by the Human Genome Project."

The work was funded by the National Institutes of Health, the National Cancer Institute, and the Leukemia Society of America.


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