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

Author

Listed:
  • Arianna Penzo

    (Université Paris Cité, CNRS, Institut Jacques Monod)

  • Marion Dubarry

    (Aix Marseille University, Institut Paoli-Calmettes, Equipe Labélisée Ligue
    Univ Lyon, Université Claude Bernard Lyon 1, INSA-Lyon, CNRS, UMR5240, Microbiologie, Adaptation et Pathogénie)

  • 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)

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.

Suggested Citation

  • Arianna Penzo & Marion Dubarry & Clémentine Brocas & Myriam Zheng & Raphaël M. Mangione & Mathieu Rougemaille & Coralie Goncalves & Ophélie Lautier & Domenico Libri & Marie-Noëlle Simon & Vincent Géli, 2023. "A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41345-z
    DOI: 10.1038/s41467-023-41345-z
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    References listed on IDEAS

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    1. Karol Kramarz & Kamila Schirmeisen & Virginie Boucherit & Anissia Ait Saada & Claire Lovo & Benoit Palancade & Catherine Freudenreich & Sarah A. E. Lambert, 2020. "The nuclear pore primes recombination-dependent DNA synthesis at arrested forks by promoting SUMO removal," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Angela Taddei & Griet Van Houwe & Florence Hediger & Veronique Kalck & Fabien Cubizolles & Heiko Schober & Susan M. Gasser, 2006. "Nuclear pore association confers optimal expression levels for an inducible yeast gene," Nature, Nature, vol. 441(7094), pages 774-778, June.
    3. Karl-Uwe Reusswig & Julia Bittmann & Martina Peritore & Mathilde Courtes & Benjamin Pardo & Michael Wierer & Matthias Mann & Boris Pfander, 2022. "Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Marta San Martin-Alonso & María E. Soler-Oliva & María García-Rubio & Tatiana García-Muse & Andrés Aguilera, 2021. "Harmful R-loops are prevented via different cell cycle-specific mechanisms," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Paula Aguilera & Jenna Whalen & Christopher Minguet & Dmitri Churikov & Catherine Freudenreich & Marie-Noëlle Simon & Vincent Géli, 2020. "The nuclear pore complex prevents sister chromatid recombination during replicative senescence," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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    1. Ebru Aydin & Silke Schreiner & Jacqueline Böhme & Birte Keil & Jan Weber & Bojan Žunar & Timo Glatter & Cornelia Kilchert, 2024. "DEAD-box ATPase Dbp2 is the key enzyme in an mRNP assembly checkpoint at the 3’-end of genes and involved in the recycling of cleavage factors," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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