Published online 7 September 2011 | Nature | doi:10.1038/news.2011.524

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BRCA1 mechanism may explain how other tumour suppressors work.

Women with a defective copy of the BRCA1 gene are more likely to develop breast cancer. SCOTT CAMAZINE/SCIENCE PHOTO LIBRARY

The protein encoded by the tumour-suppressor gene BRCA1 may keep breast and ovarian cancer in check by preventing transcription of repetitive DNA sequences, says a study published today in Nature1. This explanation brings together many disparate theories about how the gene functions and could also shed light on how other tumour suppressors work.

Since the discovery in the mid-1990s that defects in BRCA1 strongly predispose women to breast and ovarian cancer, researchers have suggested numerous ways in which the protein might stop cells from becoming cancerous. Some have focused on its ability to repair DNA damage, whereas others have studied how it regulates cell-cycle checkpoints, transcription or cell proliferation. But until now, no unifying theory of how these different functions might prevent breast and ovarian cancer has emerged.

The study published today "may provide an inkling of a unifying biological function of BRCA1, which could be at the heart of its tumour suppressor role", says Ashok Venkitaraman, a cancer biologist at the Hutchison-MRC Research Centre in Cambridge, UK, who was not involved in the study.

Led by Quan Zhu and Gerald Pao at the Salk Institute for Biological Studies in La Jolla, California, the group studied cells from mice that lack the Brca1 gene. Along with the usual problems attributed to defects in BRCA1 (in areas such as cell-cycle regulation and DNA repair), the researchers also found in these cells a surprising paucity of 'heterochromatic centres' — dense packages of normally untranscribed, repetitive sequences of DNA near a chromosome's centromere. Instead, these DNA regions were highly active, churning out large numbers of RNA transcripts called satellite repeats.

In normal cells, the BRCA1 protein keeps these regions silent by tagging histones, or DNA packaging proteins, with a molecule called ubiquitin. When the researchers added artificial ubiquitin–histone complexes to the mutant cells, the cells recovered, suggesting this was indeed the Brca1 gene's core function. Conversely, flooding normal cells with satellite repeats brought on hallmarks of genomic instability such as chromosome breaks and accumulating mutations – all thought to be features of BRCA1 loss in cells.

"People have found BRCA1 in many places, doing many things," says Pao. "All these processes involve heterochromatin, so maybe we have one mechanism that allows the explanation of a large number of observations people have made about BRCA1."

It's still not clear how this mechanism could explain the tumour suppressor's specificity to breast and ovarian tissue. Venkitaraman says it's possible that those tissues are, for some reason, especially sensitive to the loss of BRCA1 function.

The study may also have much broader significance, says Roger Greenberg, a cancer biologist at the University of Pennsylvania in Philadelphia, who didn't participate in the research. In January, Daniel Haber and his group at Harvard Medical School in Boston found satellite repeats produced in many different types of tumour tissue2, including those that lack BRCA1 mutations, suggesting that multiple pathways have gone awry in cancer to impair heterochromatin maintenance..

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Still, some puzzling questions remain about how satellite repeats could have such wide-reaching effects on cellular processes. "That is not at all clear," says Venkitaraman. "So these findings will drive future work."

Also, he notes, patients with BRCA1 defects initially have one mutant copy of the gene and one normal copy, then lose the functioning copy as the tumour develops. But because the researchers studied cells completely lacking Brca1, the findings do not explain why patients are initially predisposed to tumours, but rather why tumours develop after the functioning copy of BRCA1 shuts down. "We need to understand how one defective Brca1 copy can predispose people to tumors " Venkitaraman says.