CHAPEL HILL - A tumor-suppressor gene involved in breast and ovarian cancer susceptibility plays a central role in one of the body's most important mechanisms for repairing DNA when that genetic material becomes damaged, University of North Carolina at Chapel Hill researchers have discovered.
Using specially altered mouse embryo cells deficient in the gene BRCA1, the scientists found the gene directly or indirectly participates in what is called transcription-coupled repair.
"BRCA1's exact role is currently unknown, but it seems to be involved in a variety of cellular functions," said Dr. Steven A. Leadon, professor of radiation oncology at the UNC-CH School of Medicine. "This new work is important for two reasons. First, it provides probably the most direct evidence that BRCA1 is involved in DNA repair. Second, it will give us and others a useful assay, or test, to look at functional changes in the gene."
Such information is critical to knowing how cancer starts and how it might be prevented or treated more effectively, he said. Leadon compared it to understanding what various parts of a car engine do before being able to fix it.
A report on the research appears in the Aug. 14 issue of the journal Science. Besides Leadon, a member of the UNC Lineberger Comprehensive Cancer Center, authors are graduate student Lori Gowen, technicians Anna V. Avrutskaya and Anne M. Latour and Dr. Beverly H. Koller, research assistant professor of medicine.
Leadon said his laboratory has studied transcription-coupled repair for more than a decade. In that process, damage to active genes, which continuously produce proteins critical to cell function, are repaired more rapidly than damage in inactive or less active genes.
"So the cell has prioritized which regions of the genome, or total set of genes, it wants to fix first and does it through transcription-coupled repair," he said.
Gowen, Leadon and the others exposed the altered cells to three insults - ionizing radiation, hydrogen peroxide and ultraviolet light -- known to injure DNA in different ways. They then compared how well an active "housekeeping" gene known as DHFR could be repaired in the presence of either functioning BRCA1 or non-functioning BRCA1.
"We found that the normal BRCA1 gene is required for transcription-coupled repair of both ionizing radiation and hydrogen peroxide-induced damage, but not ultraviolet light damage," Gowen said. "That means it is needed to repair oxidative DNA damage when this damage occurs in active genes."
Scientists discovered the BRCA1 gene by studying genetic material from families in which breast cancer was hereditary, Gowen said. Since then, a second breast cancer gene, BRCA2, has been identified, and researchers have begun to suspect several others also promote cancer when not working properly.
How might the new UNC-CH findings affect medical research on humans? "This is the first direct evidence of a function for this tumor-suppressor gene, and it helps to explain how the gene may be involved in cancer," she said.
Note: Leadon can be reached at (919) 966-7713. Gowen can be reached at (919) 962-2159.
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Science