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ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins

Author

Listed:
  • Aina Maria Mas

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Enrique Goñi

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Igor Ruiz de los Mozos

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Aida Arcas

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Luisa Statello

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Jovanna González

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Lorea Blázquez

    (The Francis Crick Institute
    Biodonostia Health Research Institute
    Ikerbasque, Basque Foundation for Science)

  • Wei Ting Chelsea Lee

    (New York University School of Medicine)

  • Dipika Gupta

    (New York University School of Medicine)

  • Álvaro Sejas

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Shoko Hoshina

    (Japan Women’s University)

  • Alexandros Armaos

    (Istituto Italiano di Tecnologia)

  • Gian Gaetano Tartaglia

    (Istituto Italiano di Tecnologia
    Universitat Pompeu Fabra (UPF)
    Sapienza University of Rome
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Shou Waga

    (Japan Women’s University)

  • Jernej Ule

    (The Francis Crick Institute)

  • Eli Rothenberg

    (New York University School of Medicine)

  • María Gómez

    (Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid (CSIC/UAM))

  • Maite Huarte

    (University of Navarra
    Cancer Center Clínica Universidad de Navarra (CCUN))

Abstract

Cells must coordinate the activation of thousands of replication origins dispersed throughout their genome. Active transcription is known to favor the formation of mammalian origins, although the role that RNA plays in this process remains unclear. We show that the ORC1 subunit of the human Origin Recognition Complex interacts with RNAs transcribed from genes with origins in their transcription start sites (TSSs), displaying a positive correlation between RNA binding and origin activity. RNA depletion, or the use of ORC1 RNA-binding mutant, result in inefficient activation of proximal origins, linked to impaired ORC1 chromatin release. ORC1 RNA binding activity resides in its intrinsically disordered region, involved in intra- and inter-molecular interactions, regulation by phosphorylation, and phase-separation. We show that RNA binding favors ORC1 chromatin release, by regulating its phosphorylation and subsequent degradation. Our results unveil a non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins.

Suggested Citation

  • Aina Maria Mas & Enrique Goñi & Igor Ruiz de los Mozos & Aida Arcas & Luisa Statello & Jovanna González & Lorea Blázquez & Wei Ting Chelsea Lee & Dipika Gupta & Álvaro Sejas & Shoko Hoshina & Alexandr, 2023. "ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40105-3
    DOI: 10.1038/s41467-023-40105-3
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    1. Liana Goehring & Sarah Keegan & Sudipta Lahiri & Wenxin Xia & Michael Kong & Judit Jimenez-Sainz & Dipika Gupta & Ronny Drapkin & Ryan B. Jensen & Duncan J. Smith & Eli Rothenberg & David Fenyö & Tony, 2024. "Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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