Autophagic cell death restricts chromosomal instability during replicative crisis
Open accessAbstract
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 checkpoints 1. 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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After telomere dysfunction, some cell types may undergo apoptosis or autophagy.
“Following telomere dysfunction, some cell types may also undergo cell death by apoptosis8,9 or autophagy10.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [10]
These other cytoDNA species include those in ataxia-telangiectasia, Dnase2a deficiency, telomere damage crisis-induced CCF-like structures, HGPS nuclear abnormalities, Exo1 hyperexcision-driven chromosomal instability, and small DNA-damage associated fragments.
“These include cytoDNA in human patient-derived cells and mouse models of ataxia-telangiectasia (Song et al., 2019), Dnase2a deficiency (Lan et al., 2019; Lan et al., 2014), telomere damage crisis-induced CCF-like structures (Nassour et al., 2019), HGPS nuclear abnormalities (Kreienkamp et al., 2018), Exo1 hyperexcision-driven chromosomal instability (Guan et al., 2021), and small DNA-damage ass”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Nassour et al., 2019
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- Authors
- Nassour, J., Radford, R., Correia, A., Fusté, J. M., Schoell, B., Jauch, A., Shaw, R. J., & Karlseder, J.
- Affiliations
- Salk Institute for Biological Studies (US)
- Heidelberg University (DE)
- Corresponding author
- Karlseder, Jan
- Venue
- Nature
- Published
- 2019-01-23
- Volume
- 565
- Issue
- 7741
- Pages
- 659-663
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6557118
- OpenAlex
- W2914940244
- Cited by
- 429
- References
- 37
- Citations by year
- 2026: 39 · 2025: 43 · 2024: 66 · 2023: 56 · 2022: 46 · 2021: 70 · 2020: 68 · 2019: 41
- FWCI
- 43.58
- Type
- journal article
- Language
- en
- Update notices
- correction (2026-06-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA227934, R01CA174942, R01CA234047, P30CA014195)
- National Institute of General Medical Sciences (R01GM087476)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- autophagy, macroautophagy, chromosomal instability, telomere dysfunction, cytosolic DNA, cGAS-STING pathway, autophagic cell death, tumor suppression, oncogenic transformation, fibroblasts, epithelial cells, genomic instability
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Autophagy, Cell Line, Chromatin, DNA Damage, Epithelial Cells, Fibroblasts, Humans, Membrane Proteins, Nuclear Envelope, Nucleotidyltransferases, Telomere, Chromosomal Instability, Cell Proliferation, Cell Cycle Checkpoints, Carcinogenesis
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