Micronuclear collapse from oxidative damage

• 成果类型: Article
• 署名作者: Di Bona, Melody; Chen, Yanyang; Agustinus, Albert S.; Mazzagatti, Alice; Duran, Mercedes A.; Deyell, Matthew; Bronder, Daniel; Hickling, James; Hong, Christy; Scipioni, Lorenzo; Tedeschi, Giulia; Martin, Sara; Li, Jun; Ruzgaite, Ausrine; Riaz, Nadeem; Shah, Parin; D'Souza, Edridge K.; Brodtman, D. Zack; Sidoli, Simone; Diplas, Bill; Jalan, Manisha; Lee, Nancy Y.; Ordureau, Alban; Izar, Benjamin; Laughney, Ashley M.; Powell, Simon; Gratton, Enrico; Santaguida, Stefano; Maciejowski, John; Ly, Peter; Jeitner, Thomas M.; Bakhoum, Samuel F.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; University of Texas System; University of Texas Southwestern Medical Center; Cornell University; Weill Cornell Medicine; University of California System; University of California Irvine; University of California System; University of California Irvine; IRCCS European Institute of Oncology (IEO); Columbia University; Yeshiva University; Memorial Sloan Kettering Cancer Center; University of Milan; Cornell University; Weill Cornell Medicine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12017
• DOI: 10.1126/science.adj8691
• 发表日期: 2024-08-30
• 关键词: chromosomal instability; protein-phosphorylation; hydrogen-peroxide; dna-damage; oxygen; cancer; mechanism; transglutaminase; mitochondria; activation

摘要

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.