Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):E8900-E8908. doi: 10.1073/pnas.1805504115. Epub 2018 Sep 4.

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

Author information

1
Department of Infectious Diseases, Faculty of Life Sciences and Medicine, King's College London, SE1 9RT London, United Kingdom.
2
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112.
3
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
4
Joint Barcelona Supercomputing Center-Centre for Genomic Regulation-Institute for Research in Biomedicine Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain.
5
Program in Metabolism, Broad Institute of Harvard and MIT, Cambridge, MA 02142.
6
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142.
7
Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114.
8
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.
9
Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
10
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112; wes@biochem.utah.edu juan.martin_serrano@kcl.ac.uk.
11
Department of Infectious Diseases, Faculty of Life Sciences and Medicine, King's College London, SE1 9RT London, United Kingdom; wes@biochem.utah.edu juan.martin_serrano@kcl.ac.uk.

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, CHMP4CT232) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4CT232 allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4CT232 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 CHMP4CT232 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.

KEYWORDS:

CHMP4C; ESCRT pathway; abscission checkpoint; cancer; genome instability

PMID:
30181294
PMCID:
PMC6156662
DOI:
10.1073/pnas.1805504115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center