Novel DNA-Silencing Function of BRCA1 Discovered

It is well established that mutations in BRCA1 and BRCA2 are linked to hereditary ovarian and breast cancer; individuals with a single mutation in BRCA1 have a higher risk of developing these cancers, and these mutations can lead to shorter versions of the BRCA1 protein; prevent the protein from being made; cause a change in an amino acid that changes the function of the BRCA1 protein; or result in a deletion of a large segment of the protein.

Professor of Molecular Biology, Inder M. Verma at the Laboratory of Genetics at the Salk Institute for Biological Studies and colleagues have now identified that “maintenance of global heterochromatin integrity” is a novel function of BRCA1. The authors propose that this DNA-silencing function is linked to the role of BRCA1 as a tumor suppressor, in an article published in Nature on September 7, 2011 (doi:10.1038/nature10371). Heterochromatin is a tightly packed, mostly repetitive, nontranslated DNA sequences associated with a distinct chromatin structure that is commonly associated with gene silencing. The research suggests that deficiency in BRCA1 may cause aberrant expression of noncoding DNA that can lead to genomic instability that then promotes tumor development.

While the tumor suppressor BRCA1 has been implicated in preserving genomic stability, researchers have not yet been able to identify the biochemical activity of BRCA1 and its role in maintaining genomic integrity.

Inder Verma and colleagues have uncovered a role for BRCA1 in silencing sections of noncoding DNA, preserving the structure of heterochromatin. They show that abnormal transcription of these so-called satellite repeat regions occurs in mouse tissues and human breast cancer samples deficient in BRCA1. From these findings the authors propose that the role of BRCA1 in maintaining heterochromatin-mediated DNA silencing and genomic stability accounts for its tumor suppression functions.

Using knockout mice as a model system, the authors observed alternation of epigenetic regulation in the brain of BRCA1 knockout mice. Specifically, BRCA1 loss resulted in the derepression of tandem repeats of satellite DNA and a reduction of condensed DNA regions in the mouse genome. Additionally, the mice had a loss of ubiquitylation of histone H2A at satellite repeats. The researchers demonstrated that BRCA1 is necessary for the repression of heterochromatin by reexpressing human BRCA1 in the knockout mice.

The generation of a mammary gland-specific deletion of BRCA1 also resulted in the disruption of heterochromatin DNA in female mice, and the silencing function of BRCA1 was not limited to mouse cells, as human HeLa cells also exhibited the disregulation of constitutively silenced heterochromatin.

The DNA-silencing function of BRCA1 in humans was validated by showing the derepression of satellite transcripts in human breast tumors in BRCA mutation carriers.

The authors further showed that in the presence of wild-type BRCA1, increasing the expression of satellite DNA transcripts (derepressed heterochromatic DNA), resulted in a phenotype that partly mimics the loss of BRCA1. This indicates that the presence of constitutively silenced heterochromatin acts to prevent DNA damage and the onset of genomic instability. The high overexpression of satellite repeats has been observed in epithelial cancers.

Although the authors note that neither the function, nor the pathological significance of these satellite transcripts is known, this research suggests that satellite transcripts can contribute to the evolution of cancer through the onset of genomic instability. This study further illuminates the role of BRCA1 in preventing this type of genomic instability.