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Micronuclear collapse from oxidative damage

Affiliations
  • 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4Pharmacology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.
  • 5Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 7School of Engineering, University of California, Irvine, CA 92697, USA.
  • 8Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, CA 92617, USA.
  • 9Department of Experimental Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy.
  • 10Systems Biology Department, Columbia University, New York, NY 10032, USA.
  • 11Department of Biochemistry, Albert Einstein College of Medicine, New York, NY 10461, USA.
  • 12Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 13Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy.
  • 14Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA.

Published on:

August 29, 2024

Abstract

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.

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