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The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing

Author

Listed:
  • Philippe Coulombe

    (Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier)

  • Joelle Nassar

    (Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier)

  • Isabelle Peiffer

    (Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier)

  • Slavica Stanojcic

    (CNRS 5290 - IRD 224 - University of Montpellier (UMR “MiVEGEC”))

  • Yvon Sterkers

    (CNRS 5290 - IRD 224 - University of Montpellier (UMR “MiVEGEC”)
    University Hospital Centre (CHU), Department of Parasitology-Mycology)

  • Axel Delamarre

    (Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier)

  • Stéphane Bocquet

    (Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier)

  • Marcel Méchali

    (Institute of Human Genetics, UMR 9002, CNRS-Université de Montpellier)

Abstract

DNA replication initiation is a two-step process. During the G1-phase of the cell cycle, the ORC complex, CDC6, CDT1, and MCM2–7 assemble at replication origins, forming pre-replicative complexes (pre-RCs). In S-phase, kinase activities allow fork establishment through (CDC45/MCM2–7/GINS) CMG-complex formation. However, only a subset of all potential origins becomes activated, through a poorly understood selection mechanism. Here we analyse the pre-RC proteomic interactome in human cells and find C13ORF7/RNF219 (hereafter called OBI1, for ORC-ubiquitin-ligase-1) associated with the ORC complex. OBI1 silencing result in defective origin firing, as shown by reduced CMG formation, without affecting pre-RC establishment. OBI1 catalyses the multi-mono-ubiquitylation of a subset of chromatin-bound ORC3 and ORC5 during S-phase. Importantly, expression of non-ubiquitylable ORC3/5 mutants impairs origin firing, demonstrating their relevance as OBI1 substrates for origin firing. Our results identify a ubiquitin signalling pathway involved in origin activation and provide a candidate protein for selecting the origins to be fired.

Suggested Citation

  • Philippe Coulombe & Joelle Nassar & Isabelle Peiffer & Slavica Stanojcic & Yvon Sterkers & Axel Delamarre & Stéphane Bocquet & Marcel Méchali, 2019. "The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10321-x
    DOI: 10.1038/s41467-019-10321-x
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    Cited by:

    1. Feras E. Machour & Enas R. Abu-Zhayia & Joyce Kamar & Alma Sophia Barisaac & Itamar Simon & Nabieh Ayoub, 2024. "Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. 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.
    3. Fabian Poetz & Joshua Corbo & Yevgen Levdansky & Alexander Spiegelhalter & Doris Lindner & Vera Magg & Svetlana Lebedeva & Jörg Schweiggert & Johanna Schott & Eugene Valkov & Georg Stoecklin, 2021. "RNF219 attenuates global mRNA decay through inhibition of CCR4-NOT complex-mediated deadenylation," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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