Understanding its function helps explain how mutations in BRCA2 can lead to cancer
By LILLY ACKERMAN — science@theaggie.org
A new study from researchers at UC Davis illustrates how the Breast Cancer Gene 2 (BRCA2) protein, crucial for DNA repair, functions and how BRCA2 mutations are linked to increased rates of breast and ovarian cancer.
DNA repair is critical to maintain healthy cells and prevent cancer from developing. Cells have many pathways to prevent damaged DNA from being replicated, from direct DNA repair to programmed cell death if the damage is too severe. BRCA2 is part of a pathway that repairs damaged DNA.
Understanding how BRCA2 works can help researchers determine what exactly links mutated proteins to increased ovarian and breast cancer rates. Ultimately, the researchers hope that their findings may pave the way for future research that clinicians can use to develop therapeutics against these diseases.
Stephen Kowalczykowski, senior author on the study and distinguished professor in UC Davis’s Department of Microbiology and Molecular Genetics, said it was previously known that BRCA2 helps a different protein, RAD51, form a filament on DNA. RAD51 is another essential protein in DNA repair, and in order to function, many individual RAD51 proteins need to bind along a single strand of DNA as a filament. However, the way in which BRCA2 brings RAD51 to DNA had not been visualized prior to this study.
“What we knew is that [BRCA2] acted to assist a protein called RAD51 to form a filament on DNA,” Kowalczykowski said. “So we were hoping we would see BRCA2 doing that. In a nutshell, we did.”
The authors of the study used a device called an optical trap to visualize a single DNA molecule interacting with a single BRCA2 protein. An optical trap uses a laser focused through a high-resolution lens to form a “trap” that catches particles and holds them in place so that they can be observed in very fine detail.
By examining the interactions of BRCA2 and DNA, the authors were able to visualize just how BRCA2 helps a RAD51 filament form.
“What we actually saw was that BRCA2 enabled RAD51 to form a nucleus,” Kowalczykowski said. “So it didn’t enable growth; it enabled nucleation. Nucleation is the hard part of forming a filament. You have to start it.”
As Kowalczykowski said, the nucleation phase of filament formation is the most difficult part. Nucleation is the first phase of growth, in which a few single molecules (monomers) of RAD51 find each other by chance and begin growing. The rate of nucleation, therefore, depends on the concentration of monomers floating around.
In order to bypass the concentration-dependence of the nucleation phase, the authors found that BRCA2 acts as a chaperone for RAD51, bringing at least six RAD51 monomers at a time to the DNA strand that is in need of repair. This helps them bind together without needing to rely on chance, immediately allowing a filament to start growing.
“We propose that BRCA2 achieves this task by delivering […] a preassembled nucleus of RAD51 directly to the DNA,” the study reads. “The result would be a nascent RAD51 filament of up to eight monomers […] assembled by the chaperoning capacity of BRCA2.”
This discovery about how BRCA2 functions in the cell expands the knowledge base surrounding BRCA2 mutations and their implications for patients. While Kowalczykowski doesn’t work directly on therapeutics, this study provides insight for those that do, an important step in the advancement of treatments for cancer patients with BRCA2 mutations.
“Like anything that’s basic science, understanding the basis of the defect is step one,” Kowalczykowski said. “We personally don’t work on compounds that have therapeutic consequences, but Pharma and other labs are looking for ways to take advantage of sensitivities of BRCA1- and BRCA2-deficient cells.”
Written by: Lilly Ackerman — science@theaggie.org
