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Autophagic cell death restricts chromosomal instability during replicative crisis

Author

Listed:
  • Joe Nassour

    (The Salk Institute for Biological Studies)

  • Robert Radford

    (The Salk Institute for Biological Studies)

  • Adriana Correia

    (The Salk Institute for Biological Studies)

  • Javier Miralles Fusté

    (The Salk Institute for Biological Studies)

  • Brigitte Schoell

    (University of Heidelberg)

  • Anna Jauch

    (University of Heidelberg)

  • Reuben J. Shaw

    (The Salk Institute for Biological Studies)

  • Jan Karlseder

    (The Salk Institute for Biological Studies)

Abstract

Replicative crisis is a senescence-independent process that acts as a final barrier against oncogenic transformation by eliminating pre-cancerous cells with disrupted cell cycle checkpoints1. It functions as a potent tumour suppressor and culminates in extensive cell death. Cells rarely evade elimination and evolve towards malignancy, but the mechanisms that underlie cell death in crisis are not well understood. Here we show that macroautophagy has a dominant role in the death of fibroblasts and epithelial cells during crisis. Activation of autophagy is critical for cell death, as its suppression promoted bypass of crisis, continued proliferation and accumulation of genome instability. Telomere dysfunction specifically triggers autophagy, implicating a telomere-driven autophagy pathway that is not induced by intrachromosomal breaks. Telomeric DNA damage generates cytosolic DNA species with fragile nuclear envelopes that undergo spontaneous disruption. The cytosolic chromatin fragments activate the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) pathway and engage the autophagy machinery. Our data suggest that autophagy is an integral component of the tumour suppressive crisis mechanism and that loss of autophagy function is required for the initiation of cancer.

Suggested Citation

  • Joe Nassour & Robert Radford & Adriana Correia & Javier Miralles Fusté & Brigitte Schoell & Anna Jauch & Reuben J. Shaw & Jan Karlseder, 2019. "Autophagic cell death restricts chromosomal instability during replicative crisis," Nature, Nature, vol. 565(7741), pages 659-663, January.
  • Handle: RePEc:nat:nature:v:565:y:2019:i:7741:d:10.1038_s41586-019-0885-0
    DOI: 10.1038/s41586-019-0885-0
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    Cited by:

    1. Santiago E. Sanchez & Yuchao Gu & Yan Wang & Anudeep Golla & Annika Martin & William Shomali & Dirk Hockemeyer & Sharon A. Savage & Steven E. Artandi, 2024. "Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Natthakan Thongon & Feiyang Ma & Andrea Santoni & Matteo Marchesini & Elena Fiorini & Ashley Rose & Vera Adema & Irene Ganan-Gomez & Emma M. Groarke & Fernanda Gutierrez-Rodrigues & Shuaitong Chen & P, 2021. "Hematopoiesis under telomere attrition at the single-cell resolution," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Tobias T. Schmidt & Carly Tyer & Preeyesh Rughani & Candy Haggblom & Jeffrey R. Jones & Xiaoguang Dai & Kelly A. Frazer & Fred H. Gage & Sissel Juul & Scott Hickey & Jan Karlseder, 2024. "High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Rishi Kumar Nageshan & Raquel Ortega & Nevan Krogan & Julia Promisel Cooper, 2024. "Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Timothy K. Turkalo & Antonio Maffia & Johannes J. Schabort & Samuel G. Regalado & Mital Bhakta & Marco Blanchette & Diana C. J. Spierings & Peter M. Lansdorp & Dirk Hockemeyer, 2023. "A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.

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