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.
Micronuclear collapse from oxidative damage / M. Di Bona, Y. Chen, A.S. Agustinus, A. Mazzagatti, M.A. Duran, M. Deyell, D. Bronder, J. Hickling, C. Hong, L. Scipioni, G. Tedeschi, S. Martin, J. Li, A. Ruzgaitė, N. Riaz, P. Shah, E.K. D'Souza, D.Z. Brodtman, S. Sidoli, B. Diplas, M. Jalan, N.Y. Lee, A. Ordureau, B. Izar, A.M. Laughney, S. Powell, E. Gratton, S. Santaguida, J. Maciejowski, P. Ly, T.M. Jeitner, S.F. Bakhoum. - In: SCIENCE. - ISSN 1095-9203. - 385:6712(2024 Aug 30), pp. eadj8691.1-eadj8691.10. [10.1126/science.adj8691]
Micronuclear collapse from oxidative damage
S. Martin;S. Santaguida;
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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