A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes

Arianna Penzo, Marion Dubarry, Clémentine Brocas, Myriam Zheng, Raphaël M. Mangione, Mathieu Rougemaille, Coralie Goncalves, Ophélie Lautier, Domenico Libri, Marie-Noëlle Simon, Vincent Géli, Karine Dubrana and Benoit Palancade ()
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Arianna Penzo: Université Paris Cité, CNRS, Institut Jacques Monod
Marion Dubarry: Aix Marseille University, Institut Paoli-Calmettes, Equipe Labélisée Ligue
Clémentine Brocas: Université Paris Cité, Université Paris-Saclay, INSERM, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations
Myriam Zheng: Université Paris Cité, CNRS, Institut Jacques Monod
Raphaël M. Mangione: Université Paris Cité, CNRS, Institut Jacques Monod
Mathieu Rougemaille: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Coralie Goncalves: Université Paris Cité, CNRS, Institut Jacques Monod
Ophélie Lautier: Université Paris Cité, CNRS, Institut Jacques Monod
Domenico Libri: Univ Montpellier, CNRS
Marie-Noëlle Simon: Aix Marseille University, Institut Paoli-Calmettes, Equipe Labélisée Ligue
Vincent Géli: Aix Marseille University, Institut Paoli-Calmettes, Equipe Labélisée Ligue
Karine Dubrana: Université Paris Cité, Université Paris-Saclay, INSERM, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations
Benoit Palancade: Université Paris Cité, CNRS, Institut Jacques Monod

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Nuclear pore complexes (NPCs) have increasingly recognized interactions with the genome, as exemplified in yeast, where they bind transcribed or damaged chromatin. By combining genome-wide approaches with live imaging of model loci, we uncover a correlation between NPC association and the accumulation of R-loops, which are genotoxic structures formed through hybridization of nascent RNAs with their DNA templates. Manipulating hybrid formation demonstrates that R-loop accumulation per se, rather than transcription or R-loop-dependent damages, is the primary trigger for relocation to NPCs. Mechanistically, R-loop-dependent repositioning involves their recognition by the ssDNA-binding protein RPA, and SUMO-dependent interactions with NPC-associated factors. Preventing R-loop-dependent relocation leads to lethality in hybrid-accumulating conditions, while NPC tethering of a model hybrid-prone locus attenuates R-loop-dependent genetic instability. Remarkably, this relocation pathway involves molecular factors similar to those required for the association of stalled replication forks with NPCs, supporting the existence of convergent mechanisms for sensing transcriptional and genotoxic stresses.

Date: 2023
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DOI: 10.1038/s41467-023-41345-z

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