The chromatin-associated lncREST ensures effective replication stress response by promoting the assembly of fork signaling factors

Luisa Statello (), José Miguel Fernandez-Justel, Jovanna González, Marta Montes, Alessia Ranieri, Enrique Goñi, Aina M. Mas and Maite Huarte ()
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Luisa Statello: University of Navarra
José Miguel Fernandez-Justel: University of Navarra
Jovanna González: University of Navarra
Marta Montes: University of Navarra
Alessia Ranieri: University of Navarra
Enrique Goñi: University of Navarra
Aina M. Mas: University of Navarra
Maite Huarte: University of Navarra

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: ABSTRACT Besides the well-characterized protein network involved in the replication stress response, several regulatory RNAs have been shown to play a role in this critical process. However, it has remained elusive whether they act locally at the stressed forks. Here, by investigating the RNAs localizing on chromatin upon replication stress induced by hydroxyurea, we identified a set of lncRNAs upregulated in S-phase and controlled by stress transcription factors. Among them, we demonstrate that the previously uncharacterized lncRNA lncREST (long non-coding RNA REplication STress) is transcriptionally controlled by p53 and localizes at stressed replication forks. LncREST-depleted cells experience sustained replication fork progression and accumulate un-signaled DNA damage. Under replication stress, lncREST interacts with the protein NCL and assists in engaging its interaction with RPA. The loss of lncREST is associated with a reduced NCL-RPA interaction and decreased RPA on chromatin, leading to defective replication stress signaling and accumulation of mitotic defects, resulting in apoptosis and a reduction in tumorigenic potential of cancer cells. These findings uncover the function of a lncRNA in favoring the recruitment of replication proteins to sites of DNA replication.

Date: 2024
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DOI: 10.1038/s41467-024-45183-5

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