July 26, 2000 During the last decade, researchers have been able to confidently link mutations in the BRCA1 gene to familial breast and ovarian cancers. The actual mechanism involved, however, has eluded them. What role does BRCA1 play in health, and how do specific flaws in the gene lead to cancer?
In the July 21 issue of Cell, scientists at The Wistar Institute report that the BRCA1 protein lies at the catalytic heart of a vital DNA control complex. The complex is responsible for coordinating physical access to DNA by the cellular machinery that transcribes genes. Mutant BRCA1 would interfere with the function of the complex, so that critical genes could be inappropriately activated or inactivated. Control errors of this kind can convert a normal cell to a cancerous one.
"It may be that the entire mystery of how problems with BRCA1 lead to cancer can be explained by looking at how specific mutations interfere with the DNA control complex within which we find BRCA1," says Ramin Shiekhattar, Ph.D., an assistant professor at The Wistar Institute and senior author on the study. "Also, other proteins in the complex may themselves prove useful as screening tools for predisposition to breast and ovarian cancers."
DNA, in the form of a double helix, is a long molecular strand of genetic instructions stored in the nucleus of every cell. To keep order, nature has developed a method of tightly packaging the DNA to make genes inaccessible for transcription. The DNA wraps around small proteins called histones and then further coils into a higher order structure called chromatin. Chromatin forms into chromosomes, of which humans have 23 pairs in each cell.
The DNA control complex that incorporates BRCA1 is called SWI/SNF. SWI/SNF's role is to remodel chromatin - by uncoiling it or otherwise reshaping it - to allow the cell's transcription machinery access to the DNA. Control complexes like SWI/SNF are crucial to maintaining the orderly life of a normal cell. Estimates are that only a tenth of human genes are actively expressed at any given time, and each cell type expresses its genes in signature ways.
"In essence, these complexes loosen or unwrap the DNA to allow different cellular processes access to the genes," Shiekhattar says. "What we found was that BRCA1 is associated with one of these complexes that unpackages DNA."
The protein in the SWI/SNF complex that BRCA1 directly interacts with is called BRG1. Of the 18 proteins that constitute SWI/SNF, BRG1 is thought to be the active center of the complex with the other proteins supporting its function in different ways.
"BRG1 itself is interesting to us, because mutations in BRG1, like mutations in BRCA1, may lead to cancer," Shiekhattar notes. "Mutations in BRCA1 and another gene, BRCA2, have been linked to a high percentage of familial breast and ovarian cancers, but these represent only a small percentage - perhaps 5 percent - of these cancers overall. It may be that mutations in SWI/SNF complex proteins - BRG1 in particular - account for the unexplained majority of these cancers."
Additionally, when Shiekhattar and his team looked to see what part of BRCA1 interacted with BRG1, they found the relevant region of the protein corresponded to a stretch of the BRCA1 gene called exon 11 - a portion of the gene in which a high number of cancer-linked mutations have been found. This observation tends to confirm the significance of the findings linking BRCA1 to BRG1 and the larger SWI/SNF complex. Also, most if not all of the BRCA1 found in cells occurs in the SWI/SNF complex, suggesting the primacy of this role for BRCA1.
Daniel A. Bochar, Ph.D., is first author on the Cell paper. The other Wistar coauthors are Hideo Beniya, Ph.D., and Alexander Kinev, Ph.D. Additional coauthors are William S. Lane of Harvard University; Yutong Xue and Weidong Wang of the National Institutes of Health; and Lai Wang and Fatah Kashanchi of the UMDNJ-New Jersey Medical School. Funding for the work was provided by The W.W. Smith Charitable Trust.
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