Scientists Restore DNA Repair in Mice with Brca1 Gene Mutations
The gene BRCA1 plays an important role in repairing DNA damage that inevitably occurs as cells replicate. Through a pathway known as homologous recombination (HR), the gene helps cells make repairs and prevent further genetic changes that could set the stage for cancer.
But as a new study in mice suggests, multiple pathways may actually compete with one another to repair DNA damage within cells. The study further suggests that it may be possible to restore the HR pathway and promote faithful DNA repair in cells with BRCA1 mutations.
As a demonstration, researchers identified and then shut down an alternative DNA-repair pathway called nonhomologous end joining (NHEJ) that is associated with the protein 53BP1. This had the effect of restoring the HR pathway in a mouse model of breast cancer. These mice have targeted mutations in the Brca1 gene and normally develop mammary tumors, but deletion of the gene encoding 53BP1 prevented the formation of tumors, according to results published online in Cell on April 1.
“Our findings show that you can take cells with a deficient DNA-repair pathway and make them normal again,” said the study’s senior author, Dr. Andre Nussenzweig, who heads the Molecular Recombination Section of NCI’s Experimental Immunology Branch.
Some repair pathways, he noted, do more harm than good. While the HR pathway is essentially free of errors, the 53BP1-associated pathway produces genetic mutations that increase the risk of cancer when the BRCA1 protein is absent.
Women who inherit a defective copy of the BRCA1 gene have an approximately 80 percent chance of developing breast or ovarian cancer during their lifetimes. The researchers suggested that multiple repair pathways may coexist in cells from these women until a mutation inactivates the remaining normal copy of BRCA1. When this happens, the 53BP1 pathway takes a greater role in the response to DNA damage, leading to genetic changes and instability that are associated with cancer.
“This study shows that by controlling the types of pathways used to repair DNA in cells, we can select for error-free repair or for a more mutagenic repair pathway,” said Dr. Samuel Bunting of NCI’s Center for Cancer Research and the study’s lead author.
“We want to know whether we can prevent the genomic instability that leads to cancer in women who lose the remaining normal copy of the BRCA1 gene,” he continued. “We would like to be able to manipulate the types of pathways that cells use to repair DNA damage.”
The research team included Dr. Toren Finkel of the National Heart, Lung and Blood Institute. His group recently discovered that mice that were deficient in both the Brca1 and 53BP1 proteins were not prone to cancer, and the new results help explain why the mice did not develop tumors.
“This is a very elegant study that reveals a highly unexpected relationship between 53BP1 and BRCA1,” wrote Dr. Titia de Lange, who heads the Laboratory of Cell Biology and Genetics at Rockefeller University’s Anderson Center for Cancer Research, in an e-mail message. She was not involved in the research.
The study may also have implications for understanding mechanisms of resistance to a class of drugs called PARP inhibitors. In phase II clinical trials, these drugs have demonstrated the ability to selectively kill cells with BRCA1 mutations while largely sparing other cells. Based on the mouse study, it appears that tumors could become resistant to PARP inhibitors by inactivating 53BP1.
“Our work strongly suggests that, through the inactivation of mutagenic repair pathways, tumors could become resistant to PARP inhibitors,” noted Dr. Bunting.
The researchers are investigating whether inhibiting 53BP1 can restore the HR pathway in cells with mutations in the BRCA2 gene, which also plays a role in DNA repair.
—Edward R. Winstead