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

Ananya Acharya, Hélène Bret, Jen-Wei Huang, Martin Mütze, Martin Göse, Vera Maria Kissling, Ralf Seidel, Alberto Ciccia, Raphaël Guérois () and Petr Cejka ()
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Ananya Acharya: Faculty of Biomedical Sciences
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)
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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47936-8

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