A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

• 成果类型: Article
• 署名作者: 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; Garre, 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
• 署名单位: IRCCS European Institute of Oncology (IEO); University of Texas System; University of Texas Southwestern Medical Center; IFOM - FIRC Institute of Molecular Oncology; Fred Hutchinson Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Tel Aviv University; Tel Aviv University; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; University of Palermo; Harvard University; Harvard Medical School; University of Milan; Royal College of Surgeons - Ireland
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9170
• DOI: 10.1126/science.adj7446
• 发表日期: 2024-08-30
• 关键词: dna-damage; mis-segregation; cancer; instability; chromothripsis; aneuploidy; rupture; errors; cells

摘要

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.