Researchers at the Francis Crick Institute have outlined the structure and function of a protein complex that is required to repair damaged DNA and protect against cancer. Using cryo-electron microscopy, the researchers uncovered the atomic structure of four proteins that when mutated, play a role in inheritable breast and ovarian cancers. The proteins 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 instability in a person’s genes and cancer.

The findings are published in Nature in an article titled, “Structure and mechanism of action of the RAD51BCD-XRCC2 tumor suppressor complex.”

“Homologous recombination is a fundamental process of life, wrote the researchers. “It is required for the protection and restart of broken replication forks, the repair of chromosome breaks, and the exchange of genetic material during meiosis.”

The researchers also uncovered BCDX2’s role in the cell, finding that it acts as a “molecular chaperone”—it helps target another protein called RAD51, causing it to recognize 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 suggests that BCDX2 is just as important for repairing DNA as BRCA2, suggesting mutations should also be routinely screened for.

Luke Greenhough, PhD, co-first author and postdoctoral research assistant at the Crick, 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.”

Eric Liang, PhD, co-first author and postdoctoral fellow at the Crick, said: “Just five years ago we wouldn’t have been able to do this, the rapid advance of technology has made this research possible. DeepMind’s AlphaFold2 (a computer program that can predict a protein’s 3D structure), cryo-EM, and high-resolution imaging techniques allowed us to gather the full picture of structure and function for this key protein complex. It was a very collaborative project, spanning multiple labs and technical teams across the Crick.”

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

“Our studies demonstrate that BCDX2 orchestrates RAD51 assembly on single-stranded DNA for replication fork protection and double-strand break repair, in reactions that are critical for tumor avoidance,” concluded the researchers.

The researchers are now hoping to shed light on another protein complex, CX3, which is also involved in cancer.

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