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PreprintCited by 6DNA Repair MechanismsGenomics and Chromatin DynamicsNuclear Structure and Function

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The nucleolar protein GNL3 prevents resection of stalled replication forks

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Lebdy, Rana, Canut, Marine, Patouillard, Julie, Cadoret, Jean-Charles, Letessier, Anne, Ammar, Josiane, Basbous, Jihane, Urbach, Serge, Miotto, Benoit, Constantinou, Angelos, Abou Merhi, Raghida, Ribeyre, Cyril·2022·EMBO Reports
DOI 10.1101/2022.10.27.514025PMC PMC10702807

Preprint — published as 10.15252/embr.202357585 · Paper page

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Abstract

Summary: DNA replication requires specific proteins that protect replication forks and so prevent the formation of DNA lesions that may damage the genome. Identification of new proteins involved in these processes is essential to understand how cancer cells tolerate DNA lesions. Here we show that human GNL3/nucleostemin, a GTP-binding protein localized mostly in the nucleolus and highly expressed in cancer cells, prevents nuclease-dependent resection of nascent DNA in response to exogenous replication stress. We demonstrate that inhibition of origin firing decreases this resection, indicating that the increased replication origin firing seen upon GNL3 depletion mainly accounts for the observed DNA resection. We show that GNL3 and DNA replication initiation factor ORC2 interact in the nucleolus and that the concentration of GNL3 in the nucleolus is required to limit DNA resection in response to replicative stress. We propose that the accurate control of origin firing by GNL3, possibly through the regulation of ORC2 sub-nuclear localization, is critical to prevent nascent DNA resection in response to replication stress.

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Metadata

Authors
Lebdy, R., Canut, M., Patouillard, J., Cadoret, J.-C., Letessier, A., Ammar, J., Basbous, J., Urbach, S., Miotto, B., Constantinou, A., Abou Merhi, R., & Ribeyre, C.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Ribeyre, Cyril
ORCID
Venue
EMBO Reports
Publisher
openRxiv
Published
2022-10-30
Volume
24
Issue
12
Pages
e57585-e57585
ISSN
1469-221X (ISSN-L)
DOI
10.1101/2022.10.27.514025
PMC
PMC10702807
OpenAlex
W4388688801
Cited by
6
References
1
Citations by year
2026: 4 · 2024: 1 · 2023: 1
FWCI
0.53
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • EMBO Reports (publishedVersion, other-oa)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
Funders
  • Azm and Saade Association
  • Infrastructures en Biologie Santé et Agronomie
  • Agence Nationale de la Recherche (ANR-11-LABX-0071, 11-IDEX-005-02, ANR18, ANR-11-IDEX, ANR-17-CE12-0034, ANR-17, ANR-11-IDEX-0005, ANR-18-IDEX-0001)
  • Institut National de la Santé et de la Recherche Médicale (ANR-18-IDEX-0001)
  • Fondation pour la Recherche Médicale (AJE20151234749)
  • Fondation ARC pour la Recherche sur le Cancer (ANR-18-IDEX-0001)
  • Centre National de la Recherche Scientifique (#ANR-18-IDEX-0001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
GNL3, nucleostemin, DNA resection, replication fork protection, replication stress, nascent DNA, RPA, ORC2, origin firing, nucleolus, G proteins, DNA damage tolerance, cancer cells
MeSH terms
DNA, DNA Damage, DNA Replication, Humans, Nuclear Proteins, GTP-Binding Proteins

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