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Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells

Author

Listed:
  • Akihiro Ohashi

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Momoko Ohori

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Kenichi Iwai

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Yusuke Nakayama

    (Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited)

  • Tadahiro Nambu

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Daisuke Morishita

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Tomohiro Kawamoto

    (Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited)

  • Maki Miyamoto

    (DMPK Research Laboratories, Takeda Pharmaceutical Company Limited)

  • Takaharu Hirayama

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Masanori Okaniwa

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Hiroshi Banno

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Tomoyasu Ishikawa

    (Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited)

  • Hitoshi Kandori

    (Drug Safety Research Laboratories, Takeda Pharmaceutical Company Limited)

  • Kentaro Iwata

    (DMPK Research Laboratories, Takeda Pharmaceutical Company Limited)

Abstract

The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations—misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours.

Suggested Citation

  • Akihiro Ohashi & Momoko Ohori & Kenichi Iwai & Yusuke Nakayama & Tadahiro Nambu & Daisuke Morishita & Tomohiro Kawamoto & Maki Miyamoto & Takaharu Hirayama & Masanori Okaniwa & Hiroshi Banno & Tomoyas, 2015. "Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8668
    DOI: 10.1038/ncomms8668
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    Cited by:

    1. Lorenza Garribba & Giuseppina De Feudis & Valentino Martis & Martina Galli & Marie Dumont & Yonatan Eliezer & René Wardenaar & Marica Rosaria Ippolito & Divya Ramalingam Iyer & Andréa E. Tijhuis & Dia, 2023. "Short-term molecular consequences of chromosome mis-segregation for genome stability," Nature Communications, Nature, vol. 14(1), pages 1-17, 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.

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