Micronuclear collapse from oxidative damage Journal Article
| Authors: | Di Bona, M.; Chen, Y.; Agustinus, A. S.; Mazzagatti, A.; Duran, M. A.; Deyell, M.; Bronder, D.; Hickling, J.; Hong, C.; Scipioni, L.; Tedeschi, G.; Martin, S.; Li, J.; RuzgaiteĢ, A.; Riaz, N.; Shah, P.; D'Souza, E. K.; Brodtman, D. Z.; Sidoli, S.; Diplas, B.; Jalan, M.; Lee, N. Y.; Ordureau, A.; Izar, B.; Laughney, A. M.; Powell, S.; Gratton, E.; Santaguida, S.; Maciejowski, J.; Ly, P.; Jeitner, T. M.; Bakhoum, S. F. |
| Article Title: | Micronuclear collapse from oxidative damage |
| 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. |
| Keywords: | genetics; neoplasm; neoplasms; cell nucleus membrane; metabolism; nuclear protein; membrane proteins; pathology; hela cells; nuclear proteins; chromatin; membrane protein; reactive oxygen species; reactive oxygen metabolite; cell hypoxia; oxidative stress; mitochondria; endosomal sorting complexes required for transport; mitochondrion; oxidation reduction reaction; oxidation-reduction; cysteine; escrt protein; micronucleus; nuclear envelope; micronuclei, chromosome-defective; humans; human; hela cell line; chmp7 protein, human; lemd2 protein, human |
| Journal Title: | Science |
| Volume: | 385 |
| Issue: | 6712 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2024-08-30 |
| Start Page: | eadj8691 |
| Language: | English |
| DOI: | 10.1126/science.adj8691 |
| PUBMED: | 39208110 |
| PROVIDER: | scopus |
| PMCID: | PMC11610459 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
