DOI: 10.1101/517011Jan 10, 2019Paper

Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

BioRxiv : the Preprint Server for Biology
Marina VietriCoen Campsteijn

Abstract

The ESCRT-III membrane fission machinery restores nuclear envelope integrity during mitotic exit and interphase. Whereas primary nuclei resealing takes minutes, micronuclear envelope ruptures appear irreversible and result in catastrophic collapse associated with chromosome fragmentation and rearrangements (chromothripsis), thought to be a major driving force in cancer development. Despite its importance, the mechanistic underpinnings of nuclear envelope sealing in primary nuclei and the defects observed in micronuclei remain largely unknown. Here we show that CHMP7, the nucleator of ESCRT-III filaments at the nuclear envelope, and the inner nuclear membrane protein LEMD2 act as a compartmentalization sensor detecting the loss of nuclear integrity. In cells with intact nuclear envelope, CHMP7 is actively excluded from the nucleus to preclude its binding to LEMD2. Nuclear influx of CHMP7 results in stable association with LEMD2 at the inner nuclear membrane that licenses local polymerization of ESCRT-III. Tight control of nuclear CHMP7 levels is critical, as induction of nuclear CHMP7 mutants is sufficient to induce unrestrained growth of ESCRT-III foci at the nuclear envelope, causing dramatic membrane deformation, local DNA to...Continue Reading

Related Concepts

Cell Nucleus
Chromosomes
DNA
DNA Damage
DNA, Single-Stranded
Gene Rearrangement
Fragmentation Procedure
Local
Research Activities
Infection Surveillance

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