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Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection

Author

Listed:
  • V. Pragathi Masamsetti

    (University of Sydney)

  • Ronnie Ren Jie Low

    (University of Sydney
    The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Ka Sin Mak

    (University of Sydney)

  • Aisling O’Connor

    (University of Sydney)

  • Chris D. Riffkin

    (The Walter and Eliza Hall Institute of Medical Research)

  • Noa Lamm

    (University of Sydney)

  • Laure Crabbe

    (Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay
    Université de Toulouse, CNRS/UPS)

  • Jan Karlseder

    (The Salk Institute for Biological Studies, Molecular and Cell Biology Department)

  • David C. S. Huang

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Makoto T. Hayashi

    (Kyoto University, Yoshida-Konoe-cho, Sakyo-ku)

  • Anthony J. Cesare

    (University of Sydney)

Abstract

Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution.

Suggested Citation

  • V. Pragathi Masamsetti & Ronnie Ren Jie Low & Ka Sin Mak & Aisling O’Connor & Chris D. Riffkin & Noa Lamm & Laure Crabbe & Jan Karlseder & David C. S. Huang & Makoto T. Hayashi & Anthony J. Cesare, 2019. "Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12255-w
    DOI: 10.1038/s41467-019-12255-w
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    Cited by:

    1. Sile F. Yang & Christopher B. Nelson & Jadon K. Wells & Madushan Fernando & Robert Lu & Joshua A. M. Allen & Lisa Malloy & Noa Lamm & Vincent J. Murphy & Joel P. Mackay & Andrew J. Deans & Anthony J. , 2024. "ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Fei Li & Yizhe Wang & Inah Hwang & Ja-Young Jang & Libo Xu & Zhong Deng & Eun Young Yu & Yiming Cai & Caizhi Wu & Zhenbo Han & Yu-Han Huang & Xiangao Huang & Ling Zhang & Jun Yao & Neal F. Lue & Paul , 2023. "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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