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; Daiju Kitagawa

doi:10.1038/s41467-025-63002-3

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^*
, Daiju Kitagawa^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	7799
Number of pages	18
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	8 Sept 2025
DOIs	https://doi.org/10.1038/s41467-025-63002-3
Publication status	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-025-63002-3Licence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

MatsuhashiK2025DNAFinal published version, 13.4 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer
Stewart, G. (Principal Investigator)
Cancer Research UK
1/09/17 → 31/05/25
Project: Research

Cite this

Matsuhashi, K., Ito, K. K., Nagai, K., Sanada, A., Watanabe, K., Takumi, K., Toyoda, A., Fukuyama, M., Yamamoto, S., Chinen, T., Stewart, G. S., Hata, S., & Kitagawa, D. (2025). The DNA replication machinery transmits dual signals to prevent unscheduled licensing and execution of centrosome duplication. Nature Communications, 16(1), Article 7799. https://doi.org/10.1038/s41467-025-63002-3

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

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.",

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Matsuhashi, K, Ito, KK, Nagai, K, Sanada, A, Watanabe, K, Takumi, K, Toyoda, A, Fukuyama, M, Yamamoto, S, Chinen, T, Stewart, GS, Hata, S & Kitagawa, D 2025, 'The DNA replication machinery transmits dual signals to prevent unscheduled licensing and execution of centrosome duplication', Nature Communications, vol. 16, no. 1, 7799. https://doi.org/10.1038/s41467-025-63002-3

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AU - Matsuhashi, Kyohei

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AU - Takumi, Kasuga

AU - Toyoda, Atsushi

AU - Fukuyama, Masamitsu

AU - Yamamoto, Shohei

AU - Chinen, Takumi

AU - Stewart, Grant S.

AU - Hata, Shoji

AU - Kitagawa, Daiju

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AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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Projects

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer

Cite this