Mechanism of protection against breast and ovarian cancer

In a new paper published in Nature, researchers have outlined the structure and function of a protein complex which is required to repair damaged DNA and protect against cancer.

Every time a cell replicates, mistakes can happen in the form of mutations, but specialised proteins exist to repair the damaged DNA.

People with mutations in a DNA repair protein called BRCA2 are predisposed to breast, ovarian and prostate cancers, which often develop at a young age. In the clinic, these cancers are treated with a drug that inhibits PARP, another protein needed for DNA repair.

Recent work shows that defects in several other proteins can cause inheritable breast and ovarian cancers or Fanconi anaemia, a blood disorder that can lead to different cancers, including leukaemia.

The researchers used cryo-electron microscopy to reveal the atomic structure of four of these proteins, which come together to form a complex called BCDX2. This allowed them to map mutations associated with cancer on the 3D structure, revealing the important regions of the complex, and why certain mutations prevent DNA repair, leading to an instability in a person’s genes and cancer.

In addition, the researchers discovered BCDX2’s role in the cell, finding that it acts as a ‘molecular chaperone’ – it helps target another protein called RAD51, causing it to recognise and assemble at regions where DNA repair needs to take place. Together, BRCA2, BCDX2 and RAD51 are the main players in the process that repairs damaged DNA – called ‘homologous recombination’.

The research shows that BCDX2 is just as important for repairing DNA as BRCA2, suggesting mutations should also be routinely screened for.

A co-first author and postdoctoral research assistant, said: “For the first time, we’ve been able to show the direct links between structure, function and why mutations in any of the components of BCDX2 leads to cancer. We now understand its crucial role in DNA repair, which explains why mutations can lead to cancer.”

The research today could help inform the best line of treatment for people living with cancer.

A group leader of the DNA Recombination and Repair Laboratory, said: “BRCA2 is well characterised and known to increase the risk of cancer, especially breast and ovarian cancers. It’s mutated in 15-20% of inheritable cancer cases so is regularly screened for.

“Our research has shown that BCDX2 is also crucial for DNA repair and acts in the same pathway as BRCA2. For people with cancers caused by defects in BCDX2, PARP inhibitors are also likely to be effective. Our findings suggest that people with a family history of these cancers should be screened for mutations in the proteins making up BCDX2 to get a full picture of their risk.”

The researchers are now hoping to shed light on another protein complex, CX3, which is also involved in cancer. Putting all these insights together will allow a better understanding of genes which put people at a greater risk of cancer and help with targeted treatment.