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Mechanism of DNA unwinding by MCM8-9 in complex with HROB

Author

Listed:
  • Ananya Acharya

    (Faculty of Biomedical Sciences
    Eidgenössische Technische Hochschule (ETH))

  • Hélène Bret

    (Institute for Integrative Biology of the Cell (I2BC))

  • Jen-Wei Huang

    (Columbia University Irving Medical Center)

  • Martin Mütze

    (Universität Leipzig)

  • Martin Göse

    (Universität Leipzig)

  • Vera Maria Kissling

    (Eidgenössische Technische Hochschule (ETH)
    Swiss Federal Laboratories for Materials Science and Technology (Empa))

  • Ralf Seidel

    (Universität Leipzig)

  • Alberto Ciccia

    (Columbia University Irving Medical Center)

  • Raphaël Guérois

    (Institute for Integrative Biology of the Cell (I2BC))

  • Petr Cejka

    (Faculty of Biomedical Sciences
    Eidgenössische Technische Hochschule (ETH))

Abstract

HROB promotes the MCM8-9 helicase in DNA damage response. To understand how HROB activates MCM8-9, we defined their interaction interface. We showed that HROB makes important yet transient contacts with both MCM8 and MCM9, and binds the MCM8-9 heterodimer with the highest affinity. MCM8-9-HROB prefer branched DNA structures, and display low DNA unwinding processivity. MCM8-9 unwinds DNA as a hexamer that assembles from dimers on DNA in the presence of ATP. The hexamer involves two repeating protein-protein interfaces between the alternating MCM8 and MCM9 subunits. One of these interfaces is quite stable and forms an obligate heterodimer across which HROB binds. The other interface is labile and mediates hexamer assembly, independently of HROB. The ATPase site formed at the labile interface contributes disproportionally more to DNA unwinding than that at the stable interface. Here, we show that HROB promotes DNA unwinding downstream of MCM8-9 loading and ring formation on ssDNA.

Suggested Citation

  • Ananya Acharya & Hélène Bret & Jen-Wei Huang & Martin Mütze & Martin Göse & Vera Maria Kissling & Ralf Seidel & Alberto Ciccia & Raphaël Guérois & Petr Cejka, 2024. "Mechanism of DNA unwinding by MCM8-9 in complex with HROB," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47936-8
    DOI: 10.1038/s41467-024-47936-8
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