A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements
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.
Authors
- Melody Di Bona (ORCID: https://orcid.org/0000-0002-8853-2604)
- Alice Mazzagatti (ORCID: https://orcid.org/0000-0003-1627-0446)
- Massimiliano Garrè (ORCID: https://orcid.org/0000-0001-9332-0270)
- Simona Polo (ORCID: https://orcid.org/0000-0001-5536-9399)
- Valentino Martis
- Laura Pontano Vaites
- Alessia Loffreda (ORCID: https://orcid.org/0000-0003-4523-5666)
- Peter Ly (ORCID: https://orcid.org/0000-0001-8946-7069)
- Marica Rosaria Ippolito (ORCID: https://orcid.org/0000-0001-7310-1871)
- Uri Ben‐David (ORCID: https://orcid.org/0000-0001-7098-2378)
- Dario Parazzoli (ORCID: https://orcid.org/0000-0001-8176-9775)
- Alessandro Cuomo (ORCID: https://orcid.org/0000-0002-9778-7190)
- Galina V. Beznoussenko (ORCID: https://orcid.org/0000-0002-1876-4098)
- Fabio Bedin (ORCID: https://orcid.org/0009-0006-4313-7762)
- Stefano Santaguida (ORCID: https://orcid.org/0000-0002-1501-6190)
- Alexander A. Mirоnоv (ORCID: https://orcid.org/0000-0003-2308-1651)
- Samuel F. Bakhoum
- Gil Leor (ORCID: https://orcid.org/0000-0003-2225-5744)
- Valeria Cancila (ORCID: https://orcid.org/0000-0002-9502-1191)
- Yonatan Eliezer (ORCID: https://orcid.org/0009-0002-0515-7579)
- Emily M. Hatch (ORCID: https://orcid.org/0000-0002-3393-4075)
- Amanda Gunn (ORCID: https://orcid.org/0000-0002-9450-4976)
- Claudio Tripodo (ORCID: https://orcid.org/0000-0002-0821-6231)
- Simone Scorzoni (ORCID: https://orcid.org/0000-0003-2046-2678)
- Tal Ben-Yishay (ORCID: https://orcid.org/0009-0005-1305-0001)
- Sara Martin (ORCID: https://orcid.org/0009-0003-7289-2028)
- Maria Chiara Rainone
- Paolo Vasapolli
- Sara Cordone
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Tel Aviv University (IL)
- University of Milan (IT)
- Fred Hutch Cancer Center (US)
- Department of Health (ES)
- IFOM (IT)
- IRCCS Ospedale San Raffaele (IT)
- European Institute of Oncology (IT)
- The University of Texas Southwestern Medical Center (US)
- University of Palermo (IT)
Publication Details
- Journal
- Science
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1126/science.adj7446
- Citations
- 40
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 9.35
Funders
- Israel Cancer Research Fund
- Robertson Foundation
- Newcastle University
- Fondazione Cariplo
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Israel Cancer Association
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Cancer Institute