Sankar Mitra, Ph.D.
Background: Reactive oxygen species (ROS) are produced as byproducts of respiration and in response to infection or inflammation. Oxygen radicals are responsible for or have been implicated in a number of diseases as varied as cancer, arthritis, heart disease, Alzheimer's disease, and other sorts of degenerative neurological diseases. DNA is damaged when it comes into contact with ROS. Normally, this damage is repaired by enzymes that cleave out the damaged section and others that insert the correct genetic sequence; however, if the damage accumulates or overwhelms the repair mechanisms, disease will result.
Advance: These investigators have identified an enzyme they named NEH1 which is similar to a DNA repair enzyme found in E. coli. NEH1 appears to specialize in repairing oxidatively damaged DNA. The investigators postulate that once NEH1 recognizes a damaged section of DNA, it binds to other proteins that may already be in the damaged area. They also found that the cellular levels of the enzyme are highest, perhaps 5-10 times higher, when replication is occurring and thus errors are most likely to happen.
Implication: The discovery of this enzyme suggests the possibility that many other similar enzymes exist than were previously known. This knowledge could lead to better more targeted drugs for to improve DNA repair. The team is now engaged in creating a transgenic mouse strain lacking the NEH1 enzyme which could provide a clearer indication of its function and involvement in disease prevention. Measuring levels of the enzyme in various disease states, like cancer cells, may have implications for improved chemotherapeutic strategies.
Citation: Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW, Jaruga P, Dizdaroglu M, Mitra S. Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3523-8.