A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements-Reference-Cited by-同舟云学术

A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

Published:2024-08-30 Issue:6712 Volume:385 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Martin Sara¹^ORCID,Scorzoni Simone¹^ORCID,Cordone Sara¹,Mazzagatti Alice²^ORCID,Beznoussenko Galina V.³,Gunn Amanda L.⁴^ORCID,Di Bona Melody⁵^ORCID,Eliezer Yonatan⁶^ORCID,Leor Gil⁶^ORCID,Ben-Yishay Tal⁶⁷^ORCID,Loffreda Alessia⁸^ORCID,Cancila Valeria⁹,Rainone Maria Chiara¹,Ippolito Marica Rosaria¹^ORCID,Martis Valentino¹,Bedin Fabio¹^ORCID,Garrè Massimiliano³^ORCID,Vaites Laura Pontano¹⁰,Vasapolli Paolo¹^ORCID,Polo Simona³¹¹^ORCID,Parazzoli Dario³^ORCID,Tripodo Claudio³⁹^ORCID,Mironov Alexander A.³,Cuomo Alessandro¹^ORCID,Ben-David Uri⁶^ORCID,Bakhoum Samuel F.⁵^ORCID,Hatch Emily M.⁴^ORCID,Ly Peter²^ORCID,Santaguida Stefano¹¹¹^ORCID

Affiliation:

1. Department of Experimental Oncology at IEO, European Institute of Oncology IRCCS, Milan, Italy.

2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

3. IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.

4. Division of Basic Sciences and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

5. Human Oncology and Pathogenesis Program and Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

6. Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

7. The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.

8. Experimental Imaging Center, IRCCS Ospedale San Raffaele, Milan, Italy.

9. Tumor Immunology Unit, Department of Sciences for Health Promotion and Mother-Child Care “G. D’Alessandro,” University of Palermo, Palermo, Italy.

10. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

11. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adj7446

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