A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements
Sara Martin, Simone Scorzoni, Sara Cordone, Alice Mazzagatti, Galina V. Beznoussenko, Amanda L. Gunn, Melody Di Bona, Yonatan Eliezer, Gil Leor, Tal Ben-Yishay, Alessia Loffreda, Valeria Cancila, Maria Chiara Rainone, Marica Rosaria Ippolito, Valentino Martis, Fabio Bedin, Massimiliano Garrè, Laura Pontano Vaites, Paolo Vasapolli, Simona Polo, Dario Parazzoli, Claudio Tripodo, Alexander A. Mironov, Alessandro Cuomo, Uri Ben-David, Samuel F. Bakhoum, Emily M. Hatch, Peter Ly, Stefano SantaguidaChromosomal 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.