This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A cell's ability to repair its damaged DNA is one of the most fundamental processes in biology, helping protect us from diseases like cancer. Over the years, researchers have unraveled many of the mechanisms cells use to repair DNA, ultimately leading to precision cancer treatments.
But for more than two decades, a particular set of repair proteins, known as the RAD51 paralogs, has remained at the edge of our understanding. Mutations in these genes are linked to breast and ovarian cancer, as well as Fanconi anemia—a rare, life-limiting disorder that can cause cancer. "The RAD51 paralogs operate in the same biological pathway as well-known DNA repair genes BRCA1 and BRCA2," says Stephen West, head of the Crick's DNA Recombination and Repair Laboratory.
"As a result, some cancers caused by mutations in these genes can be treated with drugs called PARP inhibitors, because they all rely on a shared defense system." Yet despite their importance, how the RAD51 paralogs functioned has remained a mystery. "It was a real gap in the field," says West. "It was impossible to investigate their biochemistry." The problem was not a lack of curiosity.
"The proteins were so difficult to work with that we'd reached a point where hardly anyone was trying to understand what they did," he says. By the early 2000s, West and his team had discovered that the RAD51 paralogs interact to form protein complexes, but further progress stalled. These complexes proved difficult to isolate in the lab, often clumping together or degrading before they could be studied.
Without a stable, soluble sample or the technology to see it, the proteins remained effectively intractable to the scientists. What changed was not a single discovery, but a quiet revolution in scientific technology. For Luke Greenhough, a researcher in West's lab, the breakthrough came by combining three technologies: AlphaFold3 software, cryo-electron microscopy (cryo-EM) and single-molecule imaging.
AlphaFold3 is an advanced AI-based system that predicts proteins' 3D structures from their amino acid sequences. Cryo-EM, on the other hand, is a powerful way to look at the 3D structures of proteins directly. The team ran an initial AlphaFold3 prediction, and this helped shape the project's direction, pointing them to explore a structure they might not otherwise have pursued.
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