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Cell Rep. 2018 Jul 17;24(3):538-545. doi: 10.1016/j.celrep.2018.06.061.

RADX Modulates RAD51 Activity to Control Replication Fork Protection.

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
2
Cancer Research Center of Marseille, CNRS UMR7258, Inserm U1068, Institut Paoli-Calmettes, Aix-Marseille Université U105, Marseille, France.
3
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: david.cortez@vanderbilt.edu.

Abstract

RAD51 promotes homologous recombination repair (HR) of double-strand breaks and acts during DNA replication to facilitate fork reversal and protect nascent DNA strands from nuclease digestion. Several additional HR proteins regulate fork protection by promoting RAD51 filament formation. Here, we show that RADX modulates stalled fork protection by antagonizing RAD51. Consequently, silencing RADX restores fork protection in cells deficient for BRCA1, BRCA2, FANCA, FANCD2, or BOD1L. Inactivating RADX prevents both MRE11- and DNA2-dependent fork degradation. Furthermore, RADX overexpression causes fork degradation that is dependent on these nucleases and fork reversal. The amount of RAD51 determines the fate of stalled replication forks, with more RAD51 required for fork protection than fork reversal. Finally, we find that RADX effectively competes with RAD51 for binding to single-stranded DNA, supporting a model in which RADX buffers RAD51 to ensure the right amount of reversal and protection to maintain genome stability.

KEYWORDS:

BRCA1; Fanconi anemia; MRE11; RAD51; RADX; fork protection; fork reversal; replication stress

PMID:
30021152
PMCID:
PMC6086571
DOI:
10.1016/j.celrep.2018.06.061
[Indexed for MEDLINE]
Free PMC Article

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