The DNA replication machinery transmits dual signals to prevent unscheduled licensing and execution of centrosome duplication

Kyohei Matsuhashi, Kei K. Ito, Kaho Nagai, Akira Sanada, Koki Watanabe, Kasuga Takumi, Atsushi Toyoda, Masamitsu Fukuyama, Shohei Yamamoto, Takumi Chinen, Grant S. Stewart, Shoji Hata () and Daiju Kitagawa ()
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Kyohei Matsuhashi: The University of Tokyo
Kei K. Ito: The University of Tokyo
Kaho Nagai: The University of Tokyo
Akira Sanada: The University of Tokyo
Koki Watanabe: The University of Tokyo
Kasuga Takumi: The University of Tokyo
Atsushi Toyoda: National Institute of Genetics
Masamitsu Fukuyama: The University of Tokyo
Shohei Yamamoto: The University of Tokyo
Takumi Chinen: The University of Tokyo
Grant S. Stewart: University of Birmingham
Shoji Hata: The University of Tokyo
Daiju Kitagawa: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Copy number control of DNA and centrosomes is essential for accurate genetic inheritance. DNA replication and centrosome duplication have been recognized as parallel key events for cell division. Here, we discover that the DNA replication machinery directly regulates the licensing and execution processes of centrosome duplication to prevent centrosome amplification. We find that the microcephaly protein DONSON couples DNA replication initiation with Cdc6 translocation to centrosomes. The Cdc6 signal prevents the precocious occurrence of centriole disengagement, the licensing step for centrosome duplication. During DNA replication, DONSON inhibits replisome disassembly by interacting with the CMG helicase, maintaining the intrinsic S/G2 checkpoint signal that blocks centriole-to-centrosome conversion, the execution step for centrosome duplication. Disruption of these dual signals causes precocious centrosome duplication and chromosome mis-segregation, observed in DONSON patient cells. Our results reveal that the DNA replication machinery not only duplicates genetic material but also controls the system for its accurate segregation.

Date: 2025
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DOI: 10.1038/s41467-025-63002-3

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