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Mol Cell. 2017 Aug 3;67(3):374-386.e5. doi: 10.1016/j.molcel.2017.06.023. Epub 2017 Jul 20.

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

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
3
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
4
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: david.cortez@vanderbilt.edu.

Abstract

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.

KEYWORDS:

BRCA2; CXorf57; PARP inhibitor; RAD51; RPA; SMARCAL1; ZRANB3; double-strand break; fork reversal; homologous recombination; replication stress

PMID:
28735897
PMCID:
PMC5548441
DOI:
10.1016/j.molcel.2017.06.023
[Indexed for MEDLINE]
Free PMC Article

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