Dungrawala Huzefa, Bhat Kamakoti P, Le Meur Rémy, Chazin Walter J, Ding Xia, Sharan Shyam K, Wessel Sarah R, Sathe Aditya A, Zhao Runxiang, Cortez David
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
Mol Cell. 2017 Aug 3;67(3):374-386.e5. doi: 10.1016/j.molcel.2017.06.023. Epub 2017 Jul 20.
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促进同源重组修复（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，但也会使细胞对癌症治疗产生超敏反应。在此，我们描述了RADX作为一种类似RPA的单链DNA结合蛋白的鉴定过程。RADX被招募到复制叉处，通过调节RAD51来防止复制叉崩溃。当RADX失活时，过量的RAD51活性会减缓复制延伸并导致双链断裂。在缺乏BRCA2的癌细胞中，RADX缺失可恢复复制叉保护，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抑制剂产生抗性。通过在复制叉处拮抗RAD51，RADX使细胞能够保持较高的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。
