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Updated: Jul 11, 2025

Direct Restart of a Replication Fork Stalled by a Head-On RNA Polymerase
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The nucleolar protein GNL3 prevents resection of stalled replication forks

Rana Lebdy1,2, Marine Canut1, Julie Patouillard1

  • 1Institut de Génétique Humaine (UMR9002), CNRS, Université de Montpellier, Montpellier Cedex 5, France.

EMBO Reports
|November 15, 2023
PubMed

Insights

Human GNL3 protein prevents DNA damage during replication stress by controlling DNA origin firing. This discovery is crucial for understanding cancer cell genome stability and lesion tolerance.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Faithful DNA replication relies on proteins that safeguard replication forks and prevent genome-damaging lesions.
  • Understanding proteins involved in DNA lesion accumulation and tolerance in cancer is essential.

Purpose of the Study:

  • To identify novel proteins involved in DNA replication fork protection.
  • To elucidate the role of human GNL3/nucleostemin in preventing DNA lesions during replication stress.

Main Methods:

  • Investigated the function of GNL3 in response to replication stress.
  • Analyzed DNA resection, origin firing, and protein interactions (GNL3 and ORC2).
  • Utilized techniques to assess GNL3 localization and its impact on replication factors.

Main Results:

  • Human GNL3 prevents nuclease-dependent resection of nascent DNA under replication stress.
  • Inhibiting origin firing reduces DNA resection, suggesting GNL3 depletion-induced origin activation drives resection.
  • GNL3 interacts with ORC2 in the nucleolus, and its nucleolar concentration limits DNA resection.

Conclusions:

  • GNL3's nucleolar localization and interaction with ORC2 are critical for limiting DNA resection.
  • GNL3 controls origin firing, sequestering ORC2 in the nucleolus to prevent nascent DNA resection during replication stress.
  • This mechanism is vital for maintaining genome stability in cancer cells.
Keywords:
DNA replication stressDNA resectionGNL3ORC2origin firing

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