RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability.

RAD51 促进同源定向修复 (HDR)、复制叉逆转和停滞叉保护。这些功能的缺陷会导致基因组不稳定和肿瘤发生，还会导致对癌症治疗的过敏。在这里，我们描述了 RADX 作为 RPA 样单链 DNA 结合蛋白的鉴定。 RADX 被招募到复制叉，通过调节 RAD51 来防止复制叉崩溃。当 RADX 失活时，过多的 RAD51 活性会减慢复制延伸并导致双链断裂。在缺乏 BRCA2 的癌细胞中，RADX 缺失可以恢复分叉保护，但不会恢复 HDR。此外，RADX 失活使 BRCA2/RAD51 通路功能降低的癌细胞对化疗和 PARP 抑制剂产生耐药性。通过在分叉处拮抗 RAD51，RADX 使细胞能够保持高 HDR 能力，同时确保 RAD51 的复制功能得到适当调节。因此，RADX 对于实现 RAD51 活性的适当平衡以维持基因组稳定性至关重要。