Micronuclear collapse from oxidative damage
Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.
Authors
- Bill H. Diplas (ORCID: https://orcid.org/0000-0001-9248-7351)
- Melody Di Bona (ORCID: https://orcid.org/0000-0002-8853-2604)
- Enrico Gratton (ORCID: https://orcid.org/0000-0002-6450-7391)
- Alice Mazzagatti (ORCID: https://orcid.org/0000-0003-1627-0446)
- Parin Shah (ORCID: https://orcid.org/0000-0003-4648-7830)
- Edridge D’Souza (ORCID: https://orcid.org/0000-0003-4664-8163)
- Mercedes A. Duran Paez (ORCID: https://orcid.org/0009-0002-9974-4095)
- Peter Ly (ORCID: https://orcid.org/0000-0001-8946-7069)
- Manisha Jalan (ORCID: https://orcid.org/0000-0002-4467-4934)
- Nadeem Riaz (ORCID: https://orcid.org/0000-0001-9873-5862)
- G Tedeschi (ORCID: https://orcid.org/0009-0000-1295-1450)
- Ashley M. Laughney (ORCID: https://orcid.org/0000-0001-9435-953X)
- Jun Li (ORCID: https://orcid.org/0000-0002-6836-2716)
- Daniel Bronder (ORCID: https://orcid.org/0000-0003-1666-2896)
- Matthew Deyell (ORCID: https://orcid.org/0009-0009-6543-1171)
- Stefano Santaguida (ORCID: https://orcid.org/0000-0002-1501-6190)
- Alban Ordureau (ORCID: https://orcid.org/0000-0002-4924-8520)
- Benjamin Izar (ORCID: https://orcid.org/0000-0003-2379-6702)
- Nancy Y. Lee (ORCID: https://orcid.org/0000-0003-3044-9522)
- James H. Hickling (ORCID: https://orcid.org/0009-0002-6677-2161)
- Samuel F. Bakhoum
- Simon N. Powell (ORCID: https://orcid.org/0000-0002-8183-4765)
- Yanyang Chen (ORCID: https://orcid.org/0000-0003-4665-9671)
- Simone Sidoli (ORCID: https://orcid.org/0000-0001-9073-6641)
- Albert S. Agustinus (ORCID: https://orcid.org/0000-0002-2700-6475)
- Christy Hong (ORCID: https://orcid.org/0000-0002-7360-5823)
- John Maciejowski (ORCID: https://orcid.org/0000-0001-8134-9308)
- Thomas M. Jeitner (ORCID: https://orcid.org/0000-0003-3856-9836)
- Lorenzo Scipioni (ORCID: https://orcid.org/0000-0003-2980-1912)
- D. Zack Brodtman (ORCID: https://orcid.org/0009-0009-6562-0626)
- Sara Martin (ORCID: https://orcid.org/0009-0003-7289-2028)
- Aušrinė Ruzgaitė
Institutions
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Milan (IT)
- University of California, Irvine (US)
- Cornell University (US)
- Irvine University (US)
- Weill Cornell Medicine (US)
- European Institute of Oncology (IT)
- Columbia University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1126/science.adj8691
- Citations
- 60
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 14.03
Funders
- Pharmaceutical Research and Manufacturers of America Foundation
- Memorial Sloan-Kettering Cancer Center
- Robertson Foundation
- National Institutes of Health
- National Cancer Institute