BRCA gene complex

BRCA gene complex

Of the more than 3 million people with breast cancer in the United States, about 10 percent carry an inherited mutation in their BRCA1 gene. A new study from the Virginia Tech Carilion Research Institute has found that breast cancer cells can trigger self-destruction of tumour-supressing BRCA1 proteins.

“There are different ways in which DNA damage can be repaired. The breast cancer susceptibility protein, BRCA1, has an interesting mechanism as a tumor suppressor,” said Deborah Kelly, an assistant professor at the Virginia Tech Carilion Research Institute and senior author on the paper. “Unfortunately, where there are mutations in BRCA1, there’s a significant decrease in its ability to repair DNA and cells are more likely to become cancerous.”

While Kelly and her team knew that mutations in BRCA1 promoted cancer, they didn’t know exactly how those changes prevented the protein from participating in DNA repair. Looking at a particularly prevalent BRCA1 mutation, they began to understand both the structural changes and the functional fallout. 

Using molecular imaging and biochemical tools, the researchers examined human cancer cells and found that mutated BRCA1 proteins were destroyed under stressful, oxidative cellular conditions. The proteins were unable to properly repair damaged DNA.

This is because cells tag mutated BRCA1 proteins for destruction using a molecule called ubiquitin. Cells destroy the ubiquitin-tagged BRCA1 proteins, and reduce their ability to repair DNA lesions caused by reactive oxygen species, more commonly known as ‘free radicals’.

“Some ubiquitin modifications actually enhance the function of proteins, but, in this case, it acts as a target for degradation,” said Kelly, who is also an assistant professor of biological sciences at Virginia Tech’s College of Science. “Compared with non-mutated BRCA1 proteins, the ubiquitination process heightens the destruction of mutated BRCA1 proteins. The levels are lowered to a point where its power to assist in genomic maintenance is compromised.”