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.
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All data generated or analysed during this study are included in this published article (and its Supplementary Information files). Reagents are available from J.K. upon reasonable request.
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Data are archived at the Salk Institute. We thank P. Adams for discussions and U. Manor and L. Andrade in the Waitt Advanced Biophotonic Core for transmission electron microscopy experiments. J.N. was supported by EMBO (ALTF213-2016) and the Hewitt Foundation. R.R. was supported by the Paul F. Glenn Center for Biology of Aging Research. The Salk Institute Cancer Center Core Grant (P30CA014195), the NIH (R01CA227934, GM087476, R01CA174942), the Donald and Darlene Shiley Chair and the Helmsley, Auen and Highland Street Foundations support J.K.
Nature thanks M. Narita and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Nature Reviews Molecular Cell Biology (2019)