DNA-bound Structures and Mutants Reveal Abasic DNA Binding by APE1 DNA Repair and Coordination

PI: Sankar Mitra
University of Texas Medical Branch, Galveston

Background: NIEHS maintains a strong presence in the field of DNA repair through its intramural and extramural research. This is one of the most dynamic areas of scientific research. DNA repair is a term used to include most DNA damaging processing mechanisms in the cell ( base excision repair, nucleotide excision repair, transcription-coupled repair, double strand break repair, recombination repair, mismatch repair). The number of genes involved in all these processes approaches 100. Many of the genes have been associated with human diseases, such as colon breast, and prostate cancer. Other genes have been implicated in the resistance of tumor cells to killing by chemotherapeutic drugs or radiation.

The paper by Mol et.al. describes work with one of the enzymes involved in base excision repair, endonuclease 1 or APE1. The researchers used X-ray crystallography to study the structure of the enzyme bound to DNA. The key finding here is that there is now more evidence suggesting that the enzymes involved in these complex systems might not work independently. That is, when one enzymatic reaction is over, the product is presented to the next enzyme in a sequential, specific pattern. This has major implications for science and therapeutics. Holding on means that the partially repaired DNA isn't loose in a cell, where it might actually be more harmful than it was before the enzyme worked on it. Tainer states that the emerging view from this work is that the individual chemical steps controlling genetic integrity are integrated like a dance where partner exchanges, steps, and timing are carefully coordinated.

Citation: Clifford D. Mol, Tadahide Izumi, Sankar Mitra, and John A. Tainer. Nature, 403: 451-456.