Gene repairs damaged DNA.(BRCA2 Gene)(Abstract)

2002 OCT 10 - (NewsRx.com & NewsRx.net) -- Structural studies of the protein produced by the BRCA2 gene, which is implicated in the development of hereditary breast and ovarian cancers, reveal that the protein is intimately involved in repairing damaged DNA.

DNA-repair proteins perform a vital function and protect against potentially catastrophic events such as cancer-causing mutations or chromosome rearrangements, which are hallmarks of tumor cells.

Howard Hughes Medical Institute investigator Nikola P. Pavletich and his colleagues at Memorial Sloan-Kettering Cancer Center used x-ray crystallography to obtain "molecular snapshots" of the BRCA2 protein. The images produced by Pavletich's team show that BRCA2 is capable of binding to DNA, a conclusion that is supported by the group's biochemical experiments. The research was published in the journal Science.

The scientists were investigating the role of BRCA2 in homologous recombination, which is one of the ways that cells repair broken chromosomes. In this type of DNA repair, broken chromosomes are fixed by using the information from a sister chromosome as a template and "splint" to guide repair. This type of DNA repair is accurate and is the optimal mode of repair in dividing cells. Prior to the studies by Pavletich and his colleagues, BRCA2 was believed to play only an indirect regulatory role in DNA repair.

"BRCA2 had been previously implicated in the control of homologous recombination, although its precise role in this process was unknown," said HHMI investigator Stephen J. Elledge, who is at Baylor College of Medicine. "The significance of the structural studies of BRCA2 by Pavletich's group is that they provide evidence for a direct and unexpected biochemical role for BRCA2 in the enzymology of homologous recombination itself. It was an elegant study that will forever change the way we think about BRCA2 and its role in breast cancer."

Elledge authored an accompanying article in Science that discusses the implications of the findings by Pavletich and his colleagues.

Pavletich's team encountered several major technical hurdles, the first of which involved producing a segment of the BRCA2 protein - called the C-terminal end. "We chose this fragment because of evidence - based on its amino acid sequence, on the fact that it is conserved in many organisms, and on the fact that it is often mutated in tumors - that it carries out an important function in homologous-recombination-mediated repair," said Pavletich.