Defects in BRCA2, a gene that otherwise suppresses tumors, are responsible for a strong familial predisposition to breast cancer. Carriers of BRCA2 mutations also are at increased risk of ovarian, prostate, pancreatic and male breast cancer.
Now a new study, featured in the Sept. 13 issue of Science, reveals that the protein made by BRCA2 is especially important in controlling damage to DNA, the double-strand molecule that houses our genetic blueprints. "The BRCA2 protein has a direct role in homologous recombination, which is a process that cells use to repair DNA double-strand breaks," said study co-author Wen-Hwa Lee, Ph.D., professor of molecular medicine and director of the Institute of Biotechnology at The University of Texas Health Science Center at San Antonio (UTHSCSA).
When a cell divides, all genetic information is copied from the parent to the daughter cell. Injury to DNA, perhaps caused by toxic metabolites or environmental agents such as gamma rays, results in breaks of the DNA molecule and incorrect copying. The damage sometimes breaks one strand of the DNA, but other times it breaks both strands. Damage to both strands is the most severe.
The BRCA2 protein is one of dozens of repair proteins in cells. An ineffective BRCA2 protein results in accumulation of more mutations as time passes. "Our DNA is under constant assault from forces within the body and from the environment," said co-author Phang-Lang Chen, Ph.D., associate professor of molecular medicine at UTHSCSA. "For women who inherit a faulty BRCA2 gene, this particular repair protein does not work well enough if at all."
The new study unveils the 3-D crystal structure of the BRCA2 protein. Understanding of the BRCA2 protein's function is very important for studying inherited breast cancers. "This finding helps to explain the basis for understanding the loss of DNA double-strand break repair in BRCA2-associated cancers," Dr. Chen said. "More importantly, this knowledge provides us a new therapeutic target to combat sporadic breast cancers as well." A cancer is called "sporadic" if it affects a person with no previous family history of the disease.
The new study also determined the crystal structure of a second gene protein called DSS1, Dr. Chen said. The DSS1 protein is involved in a rare syndrome characterized by deformities of the face and digits and other abnormalities.
Drs. Lee and Chen collaborated with X-ray crystallographers at Memorial Sloan-Kettering Cancer Center in New York. Co-authors from that institution are Drs. Nikola P. Pavletich, Haijuan Yang, Philip D. Jeffrey, Julie Miller, Elspeth Kinnucan, Yutong Sun, Nicolas H. Thoma and Ning Zheng. "This is an outstanding collaboration between two groups," Dr. Lee said. "We have thorough understanding of what is important about BRCA2 and provided the Sloan-Kettering group with the crucial idea and reagents to make this breakthrough."
The paper is the cover article in Science. "This is a very significant discovery in terms of understanding BRCA2 function," Dr. Lee said. In 1998, his group reported that a sister gene, BRCA1, is important for DNA break repair. A year later, the same UTHSCSA team reported similar findings on BRCA2.