A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage.

Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Autophagy activation has been previously reported in DNA-damaged cells, often in association with increased cellular cytotoxicity. However, we now report a mechanism by which autophagy is suppressed in the absence of cytotoxicity within cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Specifically, our studies demonstrate the DNA damage response-dependent stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that the suppression of autophagy, through a p53-proteasome-LC3 regulatory axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could provide a means for realigning proteostasis in cells undergoing DNA damage repair.