MRNIP is a replication fork protection factor

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  • Laura Bennett
  • Angharad Wilkie
  • Effrosyni Antonopoulou
  • Ilaria Ceppi
    University of the Switzerland Italian
  • Aurore Sanchez
    University of the Switzerland Italian
  • Ellen Vernon
  • Amelia Gamble
  • Katie N Myers
    University of Sheffield
  • Spencer J Collis
    University of Sheffield
  • Petr Cejka
    University of the Switzerland Italian
  • Christopher Staples
The remodeling of stalled replication forks to form four-way DNA junctions is an important component of the replication stress response. Nascent DNA at the regressed arms of these reversed forks is protected by RAD51 and the tumor suppressors BRCA1/2, and when this function is compromised, stalled forks undergo pathological MRE11-dependent degradation, leading to chromosomal instability. However, the mechanisms regulating MRE11 functions at reversed forks are currently unclear. Here, we identify the MRE11-binding protein MRNIP as a novel fork protection factor that directly binds to MRE11 and specifically represses its exonuclease activity. The loss of MRNIP results in impaired replication fork progression, MRE11 exonuclease–dependent degradation of reversed forks, persistence of underreplicated genomic regions, chemosensitivity, and chromosome instability. Our findings identify MRNIP as a novel regulator of MRE11 at reversed forks and provide evidence that regulation of specific MRE11 nuclease activities ensures protection of nascent DNA and thereby genome integrity.
Original languageEnglish
Article numbereaba5974
Number of pages10
JournalScience Advances
Issue number28
Publication statusPublished - 10 Jul 2020

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