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Cooperative assembly of p97 complexes involved in replication termination

Author

Listed:
  • Olga V. Kochenova

    (Harvard Medical School, Blavatnik Institute
    Howard Hughes Medical Institute)

  • Sirisha Mukkavalli

    (Tufts University School of Medicine)

  • Malavika Raman

    (Tufts University School of Medicine)

  • Johannes C. Walter

    (Harvard Medical School, Blavatnik Institute
    Howard Hughes Medical Institute)

Abstract

The p97 ATPase extracts polyubiquitylated proteins from diverse cellular structures in preparation for destruction by the proteasome. p97 functions with Ufd1-Npl4 and a variety of UBA-UBX co-factors, but how p97 complexes assemble on ubiquitylated substrates is unclear. To address this, we investigated how p97 disassembles the CMG helicase after it is ubiquitylated during replication termination. We show that p97Ufd1-Npl4 recruitment to CMG requires the UBA-UBX protein Ubxn7, and conversely, stable Ubxn7 binding to CMG requires p97Ufd1-Npl4. This cooperative assembly involves interactions between Ubxn7, p97, Ufd1-Npl4, and ubiquitin. Another p97 co-factor, Faf1, partially compensates for the loss of Ubxn7. Surprisingly, p97Ufd1-Npl4-Ubxn7 and p97Ufd1-Npl4-Faf1 also assemble cooperatively on unanchored ubiquitin chains. We propose that cooperative and substrate-independent recognition of ubiquitin chains allows p97 to recognize an unlimited number of polyubiquitylated proteins while avoiding the formation of partial, inactive complexes.

Suggested Citation

  • Olga V. Kochenova & Sirisha Mukkavalli & Malavika Raman & Johannes C. Walter, 2022. "Cooperative assembly of p97 complexes involved in replication termination," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34210-y
    DOI: 10.1038/s41467-022-34210-y
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    References listed on IDEAS

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    1. Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Ann Schirin Mirsanaye & Saskia Hoffmann & Melanie Weisser & Andreas Mund & Blanca Lopez Mendez & Dimitris Typas & Johannes Boom & Bente Benedict & Ivo A. Hendriks & Michael Lund Nielsen & Hemmo Meyer , 2024. "VCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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