The nucleolar protein GNL3 prevents resection of stalled replication forks.

Rana Lebdy, Marine Canut, Julie Patouillard, Jean-Charles Cadoret, Anne Letessier, Josiane Ammar, Jihane Basbous, Serge Urbach, Benoit Miotto, Angelos Constantinou, Raghida Abou Merhi, Cyril Ribeyre

EMBO reports 2023 Dec 06

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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. © 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Citation

Rana Lebdy, Marine Canut, Julie Patouillard, Jean-Charles Cadoret, Anne Letessier, Josiane Ammar, Jihane Basbous, Serge Urbach, Benoit Miotto, Angelos Constantinou, Raghida Abou Merhi, Cyril Ribeyre. The nucleolar protein GNL3 prevents resection of stalled replication forks. EMBO reports. 2023 Dec 06;24(12):e57585