New research has uncovered how certain proteins help cells repair damaged DNA, a crucial process that protects against diseases like cancer. DNA repair is one of the most vital biological functions, and understanding its mechanisms has led to more precise cancer treatments. However, for over two decades, a group of proteins called the RAD51 paralogs has remained poorly understood. Mutations in these proteins are linked to breast and ovarian cancer, as well as Fanconi anemia, a rare and serious condition that can increase cancer risk. These proteins work alongside well-known DNA repair genes such as BRCA1 and BRCA2, and some cancers caused by mutations in these genes can be treated with drugs called PARP inhibitors. Despite this, the exact role of the RAD51 paralogs in DNA repair was unclear. Stephen West, who leads the DNA Recombination and Repair Laboratory at the Crick, explains that the RAD51 paralogs were difficult to study. “It was a real gap in the field,” he says. “It was impossible to investigate their biochemistry.” The proteins were so hard to work with that few scientists tried to study them. By the early 2000s, West and his team had shown that the RAD51 paralogs interact to form protein complexes, but further progress was limited. These complexes were hard to isolate in the lab, often clumping together or breaking down before they could be studied. Without stable samples or the right technology, the proteins remained a scientific mystery. What changed was not a single discovery, but a series of new scientific tools. Luke Greenhough, a researcher in West’s lab, used three key technologies: AlphaFold3 software, cryo-electron microscopy (cryo-EM), and single-molecule imaging. AlphaFold3 is an AI-based system that predicts the 3D structure of proteins from their amino acid sequences. Cryo-EM allows scientists to directly observe the 3D structures of proteins, and recent advances have made it possible to study complex protein clusters in great detail. Single-molecule imaging lets researchers watch individual proteins interact with DNA in real time. Together, these tools allowed the team to finally see how the RAD51 paralogs function. The results, published in two papers in 2023 and 2026, show that the RAD51 paralogs form two distinct but related complexes, each made up of four subunits. This corrects earlier assumptions that underestimated their complexity. The researchers also found that these complexes assemble and stabilize DNA repair filaments, playing a key role in fixing damaged genetic material. The findings, published in the journal Science, have important implications for understanding how mutations in these proteins can weaken DNA repair and lead to cancer. “By mapping the precise structural effects of these mutations, our work helps explain why they lead to disease,” says Greenhough. West adds that this breakthrough was only possible due to recent technological advances and Greenhough’s persistence in tackling the challenge.