Abstract
Autophagic cell death during replicative crisis prevents further accumulation of genomic instability.
Major finding: Autophagic cell death during replicative crisis prevents further accumulation of genomic instability.
Mechanism: Telomere damage generates cytosolic DNA that activates the cGAS–STING pathway and stimulates autophagy.
Impact: Autophagy may be required to eliminate precancerous cells and prevent oncogenic transformation.
Cells with dysfunctional cell-cycle checkpoints continue to undergo cell division until their telomeres become critically short, at which point telomeres become deprotected and fuse and cells undergo cell death in a process known as replicative crisis. Individual cells that escape replicative crisis accumulate increasing levels of chromosomal instability and can potentially acquire properties of transformed cells, suggesting that cell death during replicative crisis is tumor-suppressive, but the underlying mechanisms of cell death in this process are unclear. Nassour and colleagues disrupted p53- and RB1-dependent cell cycle checkpoints in human fibroblasts and epithelial cells and observed that cell death during replicative crisis was associated with hallmarks of autophagy and not apoptosis. Moreover, knockdown of essential autophagy proteins allowed cells to continue proliferating and bypass crisis in association with reduced cell death. Autophagy-deficient cells that had bypassed replicative crisis developed high levels of telomere damage and chromosomal alterations, suggesting that autophagic cell death during replicative crisis prevents genomic instability. Telomere dysfunction–induced damage specifically induced autophagy, as it generated cytosolic DNA that activated the DNA-sensing cGAS–STING pathway, which was required for both replicative crisis and autophagic cell death. Although further work is needed to confirm whether bypass of replicative crisis in nontransformed cells caused by loss of autophagy drives genome instability and tumorigenesis in vivo, this and other studies showing that autophagy can play tumor-suppressive roles in certain contexts suggest that patients receiving autophagy inhibitors as cancer therapies may have an increased risk of secondary malignancies.
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