Abstract

The repair of DNA double-strand breaks by homologous recombination is essential for genomic integrity, and its dysregulation is a hallmark of cancer 1 . Central to homologous recombination is the RAD51 recombinase, whose assembly into a nucleoprotein filament is governed by five RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3) 2 . Mutations in any of these proteins predispose individuals to multiple cancers or genetic disorders 3 , 4 , 5 , 6 . These paralogues are thought to form two functionally separate complexes RAD51B–RAD51C–RAD51D–XRCC2 (BCDX2) and RAD51C–XRCC3 (CX3), that act independently at different stages of homologous recombination 7 , 8 , 9 , 10 , 11 . Here we demonstrate that all five paralogues can assemble into a single, ATP-dependent BCDX2–CX3–RAD51 supercomplex. The architecture of this assembly bound to single-stranded DNA reveals a contiguous filament where the CX3 module stacks atop BCDX2, creating a protofilament template for RAD51 filament formation. We further identify a novel, RAD51B-independent DX2–CX3 complex (RAD51D–XRCC2–RAD51C–XRCC3) functioning as a stable RAD51 anchor on single-stranded DNA, and we capture it in multiple states, including capping RAD51 filament segment. These distinct assemblies are differentially regulated by ATPase activity, defining a dynamic BCDX2–CX3 ‘loader’ and a stable DX2–CX3 ‘anchor’ that provide functional modularity to the homologous recombination machinery. This work provides a unifying mechanism for human RAD51 paralogue function and delivers an atomic blueprint for interpreting disease-causing mutations.

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