The ESCRT-III membrane fission machinery maintains the integrity of the nuclear envelope. Although primary nuclei resealing takes minutes, micronuclear envelope ruptures seem to be irreversible. Instead, micronuclear ruptures result in catastrophic membrane collapse and are associated with chromosome fragmentation and chromothripsis, complex chromosome rearrangements thought to be a major driving force in cancer development. Here we use a combination of live microscopy and electron tomography, as well as computer simulations, to uncover the mechanism underlying micronuclear collapse. We show that, due to their small size, micronuclei inherently lack the capacity of primary nuclei to restrict the accumulation of CHMP7–LEMD2, a compartmentalization sensor that detects loss of nuclear integrity. This causes unrestrained ESCRT-III accumulation, which drives extensive membrane deformation, DNA damage and chromosome fragmentation. Thus, the nuclear-integrity surveillance machinery is a double-edged sword, as its sensitivity ensures rapid repair at primary nuclei while causing unrestrained activity at ruptured micronuclei, with catastrophic consequences for genome stability.

ESCRT-III 膜裂变机制保持核膜的完整性。虽然初级核重新密封需要几分钟，但微核包膜破裂似乎是不可逆的。相反，微核破裂导致灾难性的膜塌陷，并与染色体断裂和染色体碎裂有关，复杂的染色体重排被认为是癌症发展的主要驱动力。在这里，我们结合使用实时显微镜和电子断层扫描以及计算机模拟来揭示微核崩溃的机制。我们表明，由于它们的体积小，微核本身缺乏初级核的能力来限制 CHMP7-LEMD2 的积累，CHMP7-LEMD2 是一种检测核完整性丧失的区室化传感器。这会导致无限制的 ESCRT-III 积累，这会导致广泛的膜变形、DNA 损伤和染色体断裂。因此，核完整性监测机制是一把双刃剑，因为它的敏感性确保了初级核的快速修复，同时在破裂的微核处引起不受限制的活动，对基因组稳定性造成灾难性后果。