RADX prevents genome instability by confining replication fork reversal to stalled forks

Archana Krishnamoorthy, Jessica Jackson, Taha Mohamed, Madison Adolph, Alessandro Vindigni, David Cortez

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

RAD51 facilitates replication fork reversal and protects reversed forks from nuclease degradation. Although potentially a useful replication stress response mechanism, unregulated fork reversal can cause genome instability. Here we show that RADX, a single-strand DNA binding protein that binds to and destabilizes RAD51 nucleofilaments, can either inhibit or promote fork reversal depending on replication stress levels. RADX inhibits fork reversal at elongating forks, thereby preventing fork slowing and collapse. Paradoxically, in the presence of persistent replication stress, RADX localizes to stalled forks to generate reversed fork structures. Consequently, inactivating RADX prevents fork-reversal-dependent telomere dysfunction in the absence of RTEL1 and blocks nascent strand degradation when fork protection factors are inactivated. Addition of RADX increases SMARCAL1-dependent fork reversal in conditions in which pre-binding RAD51 to a model fork substrate is inhibitory. Thus, RADX directly interacts with RAD51 and single-strand DNA to confine fork reversal to persistently stalled forks.

Original languageEnglish
Pages (from-to)3007-3017.e5
JournalMolecular cell
Volume81
Issue number14
DOIs
StatePublished - Jul 15 2021

Keywords

  • BRCA2
  • DNA damage
  • DNA repair
  • DNA replication
  • electron microscopy
  • genome instability
  • telomere

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