BCDX2-CX3 and DX2-CX3 complexes assemble and stabilize RAD51 filaments.
basic_science · Level V
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- Record sourced from PubMed, PMID 41772053.
- Also identified by DOI 10.1038/s41586-026-10314-z.
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Abstract
The repair of DNA double-strand breaks by homologous recombination is essential for genomic integrity, and its dysregulation is a hallmark of cancer<sup>1</sup>. 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)<sup>2</sup>. Mutations in any of these proteins predispose individuals to multiple cancers or genetic disorders<sup>3-6</sup>. 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<sup>7-11</sup>. 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.