A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4C) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4C allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4C exhibit increased levels of DNA damage and are sensitized to several conditions that increase chromosome missegregation, including DNA replication stress, inhibition of the mitotic checkpoint, and loss of p53. Our data demonstrate the biological importance of the abscission checkpoint and suggest that dysregulation of abscission by CHMP4C may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.

Year of Publication
2018
Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
38
Pages
E8900-E8908
Date Published
2018 09 18
ISSN
1091-6490
DOI
10.1073/pnas.1805504115
PubMed ID
30181294
PubMed Central ID
PMC6156662
Links
Grant list
R01 GM112080 / GM / NIGMS NIH HHS / United States
102871/Z/13/Z / WT_ / Wellcome Trust / United Kingdom
DH_ / Department of Health / United Kingdom
WT_ / Wellcome Trust / United Kingdom
P30 CA042014 / CA / NCI NIH HHS / United States
S10 OD018210 / OD / NIH HHS / United States
S10 RR024761 / RR / NCRR NIH HHS / United States
WT102871MA / WT_ / Wellcome Trust / United Kingdom
P41 GM103393 / GM / NIGMS NIH HHS / United States