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Unrestrained ESCRT-III drives micronuclear catastrophe and chromosome fragmentation
Marina Vietri1,2, Sebastian W Schultz1,2, Aurélie Bellanger3
1Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.
Abstract:
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.
Insights
Ruptured micronuclei, unlike primary nuclei, undergo irreversible collapse due to uncontrolled ESCRT-III accumulation. This leads to DNA damage and chromosome fragmentation, impacting genome stability and potentially driving cancer.
Area of Science:
- Cell Biology
- Genomics
- Cancer Biology
Background:
- The ESCRT-III machinery is crucial for nuclear envelope integrity and repair.
- Micronuclear envelope ruptures, unlike those in primary nuclei, lead to catastrophic collapse and genome instability.
- Chromothripsis, a complex chromosomal rearrangement, is linked to micronuclear rupture and cancer development.
Purpose of the Study:
- To elucidate the mechanism behind micronuclear collapse following rupture.
- To investigate why micronuclear envelope ruptures are irreversible and lead to genome fragmentation.
- To understand the role of CHMP7-LEMD2 and ESCRT-III in micronuclear integrity.
Main Methods:
- Live microscopy
- Electron tomography
- Computer simulations
Main Results:
- Micronuclei, due to their small size, cannot restrict CHMP7-LEMD2 accumulation.
- Unrestrained ESCRT-III accumulation causes extensive membrane deformation and DNA damage.
- Micronuclear collapse results in chromosome fragmentation and chromothripsis.
Conclusions:
- The nuclear integrity surveillance machinery has distinct outcomes in primary nuclei versus micronuclei.
- Uncontrolled ESCRT-III activity in micronuclei leads to catastrophic genome instability.
- Micronuclear rupture and subsequent genome fragmentation are implicated in cancer development.
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