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Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1

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Listed:
  • Devashish Dwivedi

    (University of Geneva
    University of Geneva)

  • Daniela Harry

    (University of Geneva
    University of Geneva)

  • Patrick Meraldi

    (University of Geneva
    University of Geneva)

Abstract

A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress typically seen in cancer cells causes premature centriole disengagement in untransformed mitotic human cells, leading to transient multipolar spindles that favour chromosome missegregation. How mild replication stress accelerates the centrosome cycle at the molecular level remained, however, unclear. Using ultrastructure expansion microscopy, we show that mild replication stress induces premature centriole disengagement already in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. This results in a sub-critical Plk1 kinase activity that primes the pericentriolar matrix for Separase-dependent disassembly but is insufficient for rapid mitotic entry, causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity for the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.

Suggested Citation

  • Devashish Dwivedi & Daniela Harry & Patrick Meraldi, 2023. "Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41753-1
    DOI: 10.1038/s41467-023-41753-1
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    References listed on IDEAS

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    1. Anil Shukla & Dong Kong & Meena Sharma & Valentin Magidson & Jadranka Loncarek, 2015. "Plk1 relieves centriole block to reduplication by promoting daughter centriole maturation," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    2. Therese Wilhelm & Anna-Maria Olziersky & Daniela Harry & Filipe De Sousa & Helène Vassal & Anja Eskat & Patrick Meraldi, 2019. "Mild replication stress causes chromosome mis-segregation via premature centriole disengagement," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Christopher Thomas & Benjamin Wetherall & Mark D. Levasseur & Rebecca J. Harris & Scott T. Kerridge & Jonathan M. G. Higgins & Owen R. Davies & Suzanne Madgwick, 2021. "A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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