A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

• Published in: Science (American Association for the Advancement of Science) Vol. 385; no. 6712; p. eadj7446
• Main Authors: Martin, Sara, Scorzoni, Simone, Cordone, Sara, Mazzagatti, Alice, Beznoussenko, Galina V, Gunn, Amanda L, Di Bona, Melody, Eliezer, Yonatan, Leor, Gil, Ben-Yishay, Tal, Loffreda, Alessia, Cancila, Valeria, Rainone, Maria Chiara, Ippolito, Marica Rosaria, Martis, Valentino, Bedin, Fabio, Garrè, Massimiliano, Vaites, Laura Pontano, Vasapolli, Paolo, Polo, Simona, Parazzoli, Dario, Tripodo, Claudio, Mironov, Alexander A, Cuomo, Alessandro, Ben-David, Uri, Bakhoum, Samuel F, Hatch, Emily M, Ly, Peter, Santaguida, Stefano
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 30-08-2024
• Subjects: Abnormalities; Adenosine monophosphate; AMP; Autophagy; Cancer; Cell Line, Tumor; Chemoresistance; Chromosomal Instability; Chromosome rearrangements; Chromosomes; Chromothripsis; Collapse; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclic GMP; Cytosol; Damage; Deoxyribonucleic acid; Deregulation; DNA; DNA Damage; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - metabolism; Frequency stability; Genetic abnormalities; Genomic instability; Humans; Inflammation; Integrity; Localization; Mass spectrometry; Mass spectroscopy; Membranes; Metastases; Micronuclei; Micronuclei, Chromosome-Defective; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Nuclear Envelope - metabolism; Nuclear fuels; Nuclear membranes; Nuclei (cytology); Oligomerization; Oxidation; Oxygen enrichment; Prognosis; Protein composition; Proteins; Reactive oxygen species; Repair; Rupture; Rupturing; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Stimulators; Structural stability; Tumors
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adj7446

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.