Micronuclear collapse from oxidative damage

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-08-30 DOI:10.1126/science.adj8691

Melody Di Bona, Yanyang Chen, Albert S. Agustinus, Alice Mazzagatti, Mercedes A. Duran, Matthew Deyell, Daniel Bronder, James Hickling, Christy Hong, Lorenzo Scipioni, Giulia Tedeschi, Sara Martin, Jun Li, Aušrinė Ruzgaitė, Nadeem Riaz, Parin Shah, Edridge K. D’Souza, D. Zack Brodtman, Simone Sidoli, Bill Diplas, Manisha Jalan, Nancy Y. Lee, Alban Ordureau, Benjamin Izar, Ashley M. Laughney, Simon Powell, Enrico Gratton, Stefano Santaguida, John Maciejowski, Peter Ly, Thomas M. Jeitner, Samuel F. Bakhoum

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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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氧化损伤导致的微核崩溃

含染色体的微核是侵袭性癌症的标志。微核经常发生不可逆转的崩解，使其封闭的染色质暴露在细胞质中。微核破裂会催化染色体重排、表观遗传异常和炎症，但人们对保护微核完整性的机制却知之甚少。在这项研究中，我们发现线粒体衍生的活性氧（ROS）通过促进带电多囊体蛋白 7（CHMP7）的非经典功能来破坏微核，而带电多囊体蛋白 7 是膜修复复合物的支架蛋白，被称为转运所需的内体分选复合物 III（ESCRT-III）。ROS 将 CHMP7 保留在微核中，同时破坏了它与其他 ESCRT-III 成分的相互作用。ROS 诱导的半胱氨酸氧化刺激了 CHMP7 的寡聚化并与核膜蛋白 LEMD2 结合，从而破坏了微核包膜。此外，ROS-CHMP7病理轴还会导致染色体破碎，而染色体破碎正是微核破裂的结果。它还在缺氧条件下介导微核解体，将肿瘤缺氧与驱动癌症进展的下游过程联系起来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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