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

Dungrawala H, Bhat KP, Le Meur R, Chazin WJ, Ding X, Sharan SK, Wessel SR, Sathe AA, Zhao R, Cortez D
Mol Cell. 2017 67 (3): 374-386.e5

PMID: 28735897 · PMCID: PMC5548441 · DOI:10.1016/j.molcel.2017.06.023

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.

Copyright © 2017 Elsevier Inc. All rights reserved.

MeSH Terms (23)

A549 Cells Animals BRCA2 Protein CRISPR-Cas Systems DNA, Neoplasm DNA Breaks, Double-Stranded DNA Repair Dose-Response Relationship, Drug Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic Genomic Instability HEK293 Cells Humans Mice Models, Molecular Mutation Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Protein Binding Rad51 Recombinase Replication Origin RNA Interference Transfection

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