美国基因泰克公司Stanislau Yatskevich小组宣布他们研制了BCDX2-CX3和DX2-CX3配合物组装和稳定RAD51细丝。这一研究成果于2026年3月2日发表在国际顶尖学术期刊《自然》上。

该课题组人员证明了这五个类似物可以组装成一个单一的ATP依赖的BCDX2-CX3-RAD51超复合物。这种与单链DNA （ssDNA）结合的组装结构揭示了一个连续的丝状结构，其中CX3模块堆叠在BCDX2上，为RAD51丝状结构创建了一个原丝模板。该课题组研究人员进一步确定了一种新的，不依赖于RAD51D的DX2-CX3复合物（RAD51D-XRCC2-RAD51C-XRCC3），作为稳定的RAD51锚定在ssDNA上，并在多种状态下捕获它，包括覆盖RAD51丝段。这些不同的组装受到ATP酶活性的不同调节，定义了一个动态的BCDX2-CX3“装载器”和一个稳定的DX2-CX3“锚”，为HR机制提供功能模块化。这项工作提供了人类RAD51平行功能的统一机制，并提供了解释疾病引导突变的原子蓝图。

据悉，同源重组（HR）修复DNA双链断裂对基因组完整性至关重要，其失调是癌症的一个标志。HR的核心是RAD51重组酶，其组装成核蛋白丝是由RAD51的五个类似物（RAD51B, RAD51C, RAD51D, XRCC2, XRCC3）控制的。这些蛋白质中的任何一种发生突变都会使个体易患多种癌症或遗传疾病。这些类似物被认为形成了两个功能独立的复合物，BCDX2 （RAD51B-C-D-XRCC2）和CX3 (RAD51C-XRCC3)，它们在HR7-11的不同阶段独立起作用。

附：英文原文

Title: BCDX2–CX3 and DX2–CX3 complexes assemble and stabilize RAD51 filaments

Author: Koo, Christopher W., Xiao, Jiaqi, Coassolo, Sebastien, Liu, Jie, Yu, Christine, Azumaya, Caleigh, Gore, Steven K., Cheung, Tommy K., Brillantes, Bobby, Rose, Chris M., Heyer, Wolf-Dietrich, Ciferri, Claudio, Yatskevich, Stanislau

Issue&Volume: 2026-03-02

Abstract: The repair of DNA double-strand breaks by homologous recombination (HR) is essential for genomic integrity, and its dysregulation is a hallmark of cancer1. Central to HR is the RAD51 recombinase, whose assembly into a nucleoprotein filament is governed by five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3)2. Mutations in any of these proteins predispose individuals to multiple cancers or genetic disorders3-6. These paralogs are thought to form two functionally separate complexes, BCDX2 (RAD51B-C-D-XRCC2) and CX3 (RAD51C-XRCC3), that act independently at different stages of HR7-11. Here, we demonstrate that all five paralogs can assemble into a single, ATP-dependent BCDX2-CX3-RAD51 supercomplex. The architecture of this assembly bound to single-stranded DNA (ssDNA) 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 ssDNA, 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 HR machinery. This work provides a unifying mechanism for human RAD51 paralog function and delivers an atomic blueprint for interpreting disease-causing mutations.

DOI: 10.1038/s41586-026-10314-z

Source: https://www.nature.com/articles/s41586-026-10314-z