A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.

Sara Martin Simone ScorzoniSara CordoneAlice MazzagattiGalina V BeznoussenkoAmanda L Gunn Melody DiBona Yonatan Eliezer Gil Leor Tal Ben-Yishay Alessia LoffredaValeria CancilaMaria Chiara RainoneMarica Rosaria IppolitoValentino MartisFabio Bedin Massimiliano GarrèLaura Pontano VaitesPaolo Vasapolli Simona Polo Dario Parazzoli Claudio TripodoAlexander A MironovAlessandro Cuomo Uri Ben-David Samuel F Bakhoum Emily M Hatch Peter Ly Stefano Santaguida

Published in: Science (New York, N.Y.) (2024)

Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)-dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.

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