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Gene defects tied to inability of cells to repair DNA damage

In new research carrying implications for human disease development, University of North Carolina scientists and others have linked gene defects to the inability of cells to repair damaged DNA.

The findings published April 13 in the journal Cell offer new insights into how cells repair the DNA damage that may occur during normal metabolism. Such naturally occurring oxidative damage promotes tissue changes thought to be associated with disease development, including cancer, heart disease and rheumatoid arthritis.

Study co-author Steven A. Leadon, Ph.D., head of molecular radiobiology at the UNC Lineberger Comprehensive Cancer Center said "oxidative damage is probably the most common type of damage humans are exposed to because we live and breath oxygen, and oxygen can be reactive and cause DNA damage." Within cells, oxidation leads to formation of free radicals, short-lived highly active particles that occur naturally during metabolism. These are also introduced into the body through smoking, inhaling environmental pollutants, or exposure to the sun's ultraviolet (UV) radiation. From numerous studies, free radicals are known to interact readily with nearby molecules to cause cellular damage, including damage to genetic material.

Damage repair to an active gene, one that continually produces proteins crucial to cellular function, normally occurs through a process known as transcription coupled repair. "We were trying to understand how defects in one of the proteins required for this process works," Leadon said. "And what we were looking at was whether or not the defect has something to do with the inability to repair oxidative damage that occurs in a gene."

In 1998, Leadon and his UNC colleagues were the first to link the defective breast cancer gene BRCA1 to the inability of cells to correct DNA oxidative damage. His work directly demonstrated that BRCA1 was required for transcription-coupled repair. Those studies involved altered cells derived fro
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Contact: Leslie H. Lang
llang@med.unc.edu
919-843-9687
University of North Carolina School of Medicine
13-Apr-2000


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