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.

中文翻译：

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氧化损伤引起的微核崩溃


包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的塌陷，将其封闭的染色质暴露在胞质溶胶中。微核破裂催化染色体重排、表观遗传异常和炎症，但保护微核完整性的机制知之甚少。在这项研究中，我们发现线粒体衍生的活性氧 （ROS） 通过促进带电多泡体蛋白 7 （CHMP7） 的非经典功能来破坏微核，CHMP7 是一种用于膜修复复合物的支架蛋白，称为运输 III 所需的内体分选复合物 （ESCRT-III）。ROS 将 CHMP7 保留在微核中，同时破坏其与其他 ESCRT-III 组分的相互作用。ROS 诱导的半胱氨酸氧化刺激 CHMP7 寡聚化并与核膜蛋白 LEMD2 结合，破坏微核包膜。此外，这个 ROS-CHMP7 病理轴导致已知由微核破裂引起的染色体破碎。它还介导了低氧条件下的微核不完整性，将肿瘤缺氧与驱动癌症进展的下游过程联系起来。