Molecular Cell
Molecular Cell
5 years ago

RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks

RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks
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.

Graphical abstract

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Teaser

Dungrawala et al. identify RADX as an RPA-like single-strand DNA binding protein enriched at replication forks. RADX antagonizes RAD51 accumulation at forks, thereby preventing aberrant fork remodeling. RADX deletion confers fork protection and chemoresistance to BRCA2 mutant cells without affecting homologous recombination repair of double-strand breaks.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304574

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