Error-prone DNA replication and repair can lead to mutations and cancer in people who inherit a mutant copy of the BRCA1 gene, according to a new study by researchers at Weill Cornell Medicine. The finding has potential implications for preventing the development of cancer in patients who carry these mutations.
The study, published Sept. 12 in Molecular Cell, provides new insight into why individuals who inherit a mutation in one copy of the BRCA1 gene often develop mutations in their remaining normal copy of the BRCA1 gene, opening up the pathway to tumor development. When the cells of these individuals are stressed, replication of the normal BRCA1 gene stops due to the highly repetitive DNA sequences in the gene that create physical barriers to the machinery that copies DNA. To repair the stall, an error-prone DNA repair mechanism comes into play.
“We have identified some of the early stages of cancer development in people with inherited BRCA1 mutations,” said study lead author Dr. Jeannine Gerhardt, assistant professor of stem cell biology in obstetrics and gynecology and at the Ronald O. Perelman and Claudia Cohen Center. for reproductive medicine at Weill Cornell Medicine.
The BRCA1 gene encodes an important DNA repair protein, explained the study’s lead author Dr. Madhura Deshpande, a research associate at the Center for Reproductive Medicine at Weill Cornell Medicine. Dr Deshpande said people who inherit one mutant and one normal copy produce about half of this DNA repair protein than people with two normal copies.
To understand why the remaining functional copy of the BRCA1 gene is often mutated as well, the team studied DNA replication in human embryonic stem cells as well as in human breast epithelial cells with a mutant copy of the BRCA1 gene. Human embryonic stem cells were generated at the Center for Reproductive Medicine by Dr. Nikica Zaninovic and Dr. Zev Rosenwaks. They exposed the cells to a chemical to mimic environmental stress on the cells. They discovered that when the DNA in these cells unpacks into two strands to make a copy of the DNA for each new cell, the machinery that copies the DNA gets blocked at the BRCA1 gene due to the DNA sequences repeats of the gene. The team also demonstrated for what is believed to be the first time that BRCA genes are fragile and break-prone sites. Because cells only have half of the BRCA1 protein available to repair breaks, cells turn to a more error-prone backup DNA repair mechanism called microhomology-mediated break-induced replication ( MMBIR), explained Dr. Deshpande.
The team also looked at tumor cells from women with breast cancer linked to inherited BRCA1 mutations. They found mutations in the BRCA1 and BRCA2 genes, such as deletions and insertions, likely caused by the faulty MMBIR process.
“We are currently interested in finding other additional error-prone repair mechanisms that could contribute to genomic instability and mutagenesis in these cells,” Dr. Deshpande said. Dr. Gerhardt said the team was simultaneously seeking to identify the actual environmental stressors that trigger replication problems and defective DNA repair in BRCA1-related breast cancers.
The team is also working to develop strategies to prevent the use of error-prone DNA repair mechanisms in women with inherited BRCA1 mutations. For example, they are testing the protective effects of dietary compounds that are linked to a reduced risk of breast cancer in carriers of the BRCA1 mutation. If successful, they may be able to identify drugs or other interventions that could prevent cancer in women with inherited BRCA1 mutations and provide an alternative to existing invasive preventative measures such as preventative mastectomy or breast cancer. removal of the ovaries.
“I think we can step in and find compounds that will prevent patients with inherited BRCA1 mutations from accumulating mutations that lead to cancer,” Dr. Gerhardt said.
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