Individual BRCA2 proteins (smaller dark pink dots) interacting with a strand of DNA. Credit: UC Davis video
Key points:
- In recorded observations, researchers show how the gene BRCA2 repairs DNA.
- Elucidating the function of BRCA2 is essential for understanding the molecular etiology of cancer development in breast and ovarian cells.
- The connection between BRCA2 in DNA repair and mutations gives researchers more insight into cancer risk.
A new study on how the gene BRCA2 works to repair DNA might help researchers understand its connection to breast and ovarian cancer.
Our DNA is under constant assault by both processes inside cells and by outside factors, such as sunlight or chemical exposures. Accumulating damage to DNA can cause cells to become cancerous. Fortunately, our cells have several mechanisms to repair DNA—one being homologous recombination to repair double-stranded breaks.
When a break crosses both strands of the DNA double helix, one strand is trimmed back a little to leave a single exposed strand. This strand then goes hunting for its counterpart in the same gene in the matching paired chromosome. It inserts into the healthy DNA and uses it as a template for repair. For this insertion to work, the single strand of DNA has to be coated with RAD5.
That’s where BRCA2 comes in. Analyzing BRCA2 at the level of single molecules, the UC Davis team discovered that the gene acts as a molecular chaperone, delivering RAD5 to single-stranded DNA. The function of BRCA2 is to load up with RAD51 (each BRCA2 can carry up to six RAD51s), push another protein called RPA out of the way and put the proteins onto the DNA.
For the new study published in PNAS, postdoctoral researcher Jason Bell recorded the proteins and molecules as he manipulated pieces of DNA with a single-stranded gap, and exposed them to RAD51 with and without BRCA2 under different conditions. The resulting videos show exactly how BRCA2 chaperones RAD51 onto single-stranded DNA, displacing RPA.
Understanding the role of BRCA2 in DNA repair has two important implications. First, it helps us understand why mutations of BRCA2 lead to an increased risk of cancer. Second, some drugs to treat cancer work by damaging DNA. By understanding how DNA repair works, we can develop new drugs to target it specifically in cancer cells.