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Cited 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·2023·The EMBO Reports
DOI 10.15252/embr.202357585PMC PMC10702807

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Abstract

Faithful 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 this process is essential to understand how DNA lesions accumulate in cancer cells and how they tolerate them. 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 replication stress. We demonstrate that inhibiting origin firing reduces resection. This suggests that the heightened replication origin activation observed upon GNL3 depletion largely drives the observed DNA resection probably due to the exhaustion of the available RPA pool. 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. We propose that the control of origin firing by GNL3 through the sequestration of ORC2 in the nucleolus 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., 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
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2023-11-15
Volume
24
Issue
12
Pages
e57585-e57585
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.202357585
PMC
PMC10702807
OpenAlex
W4388688801
Cited by
6
References
3
Citations by year
2026: 4 · 2024: 1 · 2023: 1
FWCI
0.53
Type
journal article
Language
en
Open access
Licence
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
  • Agence Nationale de la Recherche (REPLIBLOCK ANR‐17‐CE12‐0034‐01)
  • Azm & Saade Association
  • Canceropole Grand Sud‐Ouest
  • Fondation ARC pour la Recherche sur le Cancer
  • Fondation pour la Recherche Médicale (AJE20151234749)
  • IdEx Université Paris Cité (ANR‐18‐IDEX‐0001)
  • Labex ‘Who am I?’ (ANR‐11‐LABX‐0071, ANR‐11‐IDEX‐005‐02)
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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