Science1 publisher2 min readPublished
Crick structures show how RAD51 paralogs build and cap DNA repair filaments
Crick researchers report that two four-subunit RAD51 paralog complexes assemble and cap DNA repair filaments, after about 20 years of stalled study. The genes sit in the BRCA pathway and the structures may help explain disease mutations, but the work includes no drug or patient data.
The Scientist · Science desk
What happened
- By the early 2000s, Stephen West's Crick lab had found that the RAD51 paralog proteins form complexes, but further progress on them then stalled.
- Luke Greenhough, a researcher in West's lab, combined AlphaFold3 structure prediction, cryo-electron microscopy and single-molecule imaging to study the proteins.
- Papers in 2023 and 2026 show the paralogs form two distinct but closely related complexes of four subunits each, more than earlier work had assumed.
- The 2026 paper in Science images the XRCC3-RAD51C-RAD51D-XRCC2 complex assembling RAD51 repair filaments and capping their ends.
- Mutations in the RAD51 paralog genes are linked to breast and ovarian cancer and to Fanconi anemia, a rare disorder that can cause cancer.
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Why it matters
- capability Capping the RAD51 filament is now a defined activity, so labs testing a paralog mutant have a specific function they can measure.
- constraint The work does not by itself widen PARP inhibitor use; changing who is treated would need drug-response studies in cells and patients carrying the mapped mutations.
- precedent An AI structure prediction restarted a project stalled for two decades. Labs studying other complexes that clump or degrade in the lab could try the same predict-then-image approach.
The obstacle was the sample. The paralog complexes proved hard to isolate, often clumping together or degrading before they could be studied, and without a stable, soluble sample they stayed out of reach [6]. "It was impossible to investigate their biochemistry," said Stephen West, who heads the Crick's DNA Recombination and Repair Laboratory [15]. "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 said [4].
An initial AlphaFold3 prediction pointed the team toward a structure they might not otherwise have pursued [8]. A predicted model is a hypothesis about shape. The structures in the Science paper came from cryo-EM, which images the real complex [11]. Greenhough said cryo-EM went through a "resolution revolution" in the 2010s [17]. Single-molecule imaging adds a time dimension. It "allows us to watch individual proteins interact with DNA in real time," he said [14]. Pairing a static structure with real-time recordings on DNA lets the team check a shape against a behaviour.
West put the timing down to tools. "This has been a 20-year puzzle," he said [13], crediting "technological developments in the last few years" and Greenhough's determination for the result [16].
The PARP inhibitor connection comes from West's description of the pathway. "The RAD51 paralogs operate in the same biological pathway as well-known DNA repair genes BRCA1 and BRCA2," he said [2]. "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" [3]. He gives that as the existing reason these genes matter clinically. It is not presented as a finding of the new papers. The account of the work also gives no count of the disease mutations the team mapped.
In my view the near-term value sits with mutations. A variant that falls at a subunit interface or on the capping surface is a stronger candidate for a repair defect than one that does not. A structure lets researchers make that call. "By mapping the precise structural effects of these mutations, our work helps explain why they lead to disease," Greenhough said [12].
What to watch
- Whether clinical variant classification starts using the XRCC3-RAD51C-RAD51D-XRCC2 structure to call paralog mutations found in breast and ovarian cancer patients as damaging or benign.
- Any study measuring PARP inhibitor response in cells or tumours carrying paralog mutations that the structures predict will break filament assembly or capping.