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MRNIP limits ssDNA gaps during replication stress

Laura G Bennett1, Ellen G Vernon1, Vithursha Thanendran1

  • 1North West Cancer Research Institute, North Wales Medical School, Bangor, Gwynedd, Wales LL57 2UW, UK.

Nucleic Acids Research
|June 25, 2024
PubMed

Insights

The MRE11 regulator MRNIP prevents DNA gaps during replication stress, particularly when fork reversal is impaired. MRNIP deficiency increases sensitivity to PARP inhibitors and DNA damage.

Area of Science:

  • Molecular Biology
  • DNA Replication
  • DNA Repair

Background:

  • Replication stress can lead to DNA gaps, impacting genome stability.
  • PRIMPOL-dependent repriming creates single-stranded DNA (ssDNA) gaps, linked to mutagenesis and chemosensitivity.
  • Replication fork reversal, mediated by SMARCAL1 and ZRANB3, suppresses these gaps.

Purpose of the Study:

  • Investigate the role of MRNIP in regulating ssDNA gaps during replication stress.
  • Determine MRNIP's function when replication fork reversal is compromised.

Main Methods:

  • Cellular models with perturbed fork reversal (Olaparib treatment, SMARCAL1/ZRANB3 depletion).
  • Analysis of PRIMPOL and MRE11-dependent ssDNA gap prevalence.
  • Assessment of MRNIP-deficient cell sensitivity to PARP inhibition.
  • Investigation of gap-filling mechanisms in MRNIP-deficient cells.

Main Results:

  • MRNIP limits PRIMPOL and MRE11-dependent ssDNA gaps when fork reversal is perturbed.
  • MRNIP-deficient cells exhibit sensitivity to PARP inhibition and accumulate PRIMPOL-dependent DNA damage.
  • UBC13-mediated template switching involving REV1 and Pol-ζ drives gap filling in MRNIP-deficient cells.

Conclusions:

  • MRNIP plays a pro-survival role by regulating post-replicative ssDNA gap dynamics.
  • This study identifies MRNIP as a direct MRE11 regulator modulating ssDNA gap prevalence.

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