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REHOVOT, Israel - November 12, 1997 - Researchers at the Weizmann Institute of Science have discovered that two repair proteins perform a truly "heroic" act, stopping genetic mutations dead in their tracks. In a study reported in the November 14 issue of the Journal of Biological Chemistry , Institute researchers describe how these proteins "fling themselves" onto damaged genes, which, if replicated, lead to the formation of mutations.
Mutations are changes in DNA that can cause cancer by turning on cancer-causing genes or turning off the genes that suppress cancer. "If we can fully understand this and other natural DNA repair mechanisms, we may one day be able to turn them on as required in order to prevent cancer," says research team leader Prof. Zvi Livneh of the Weizmann Institute's Department of Biological Chemistry. He conducted the study with Dr. Tamar Paz-Elizur and doctoral student Yoav Barak.
DNA damage is a normal part of the life of a cell. Carcinogens, such as ultraviolet radiation or the chemicals in cigarette smoke, routinely damage DNA, leading to numerous mutations. Luckily, DNA can repair itself, relying on proteins known as repair enzymes. These enzymes literally cut out the damaged parts of the DNA and replace them with healthy DNA material. Without them, life on earth would be impossible because mutations would go haywire.
Sometimes, however, the damaged DNA escapes repair and a cascade of events leading to cancerous growth can begin. This is precisely where our two heroic proteins, known as Fpg and UvrA, step in. These proteins were previously known to play a role in cut-and-paste DNA repair jobs. But now Prof. Livneh's team has discovered that they are capable of a far more valiant task. By hurling themselves onto the damaged DNA and physically attaching themselves to it, these proteins can prevent the damaged site from multiplying and causing a mutation. According to the scientists, the two "heroic" proteins may be part of a larger family of DNA repair proteins that work on the same principle.
This mechanism provides a second line of defense against the mutation and gives the cell a crucial second chance at healthy growth. "The proteins block the road to replication like demonstrators throwing themselves down on the road to block traffic," says Prof. Livneh. "When a protein sits on the lesion and directly binds itself onto the site of the damage, the mutation cannot be formed." Only when this emergency defense mechanism fails, can malignant transformation begin.
Building up natural defenses
Weizmann scientists discovered the new role of the two proteins by analyzing E coli bacteria. They will follow up this research by analyzing human cells, Prof. Livneh says.
Every human body contains different kinds and quantities of repair proteins. In each individual they vary in their rate of repair. When scientists learn more about these proteins - determining, for example, which proteins repair what kinds of damage - they may be able to strengthen people's own natural defenses.
Scientists may also one day be able to identify people whose bodies aren't as effective as others at repairing DNA. For example, they may be able to warn people who are more prone to genetic defects induced by ultraviolet radiation to avoid excessive exposure to sunlight.
This research was funded in part by the Scheuer Research Foundation of the Israel Academy of Sciences and Humanities, the Israel Ministry of Science, and the Leo and Julia Forchheimer Center for Molecular Genetics at the Weizmann Institute.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.