Faculty Collaboration Database

A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability. Proc Natl Acad Sci U S A 2018 Sep 18;115(38):E8900-E8908

Date

09/06/2018

Pubmed ID

30181294

Pubmed Central ID

PMC6156662

DOI

10.1073/pnas.1805504115

Scopus ID

2-s2.0-85053465437 (requires institutional sign-in at Scopus site)   42 Citations

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^T232) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4C^T232 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^T232 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^T232 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.

Author List

Sadler JBA, Wenzel DM, Strohacker LK, Guindo-Martínez M, Alam SL, Mercader JM, Torrents D, Ullman KS, Sundquist WI, Martin-Serrano J

Author

Dawn M. Wenzel PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Calcium-Binding Proteins
Carcinogenesis
Cell Cycle Checkpoints
Cell Cycle Proteins
Cell Line, Tumor
Chromatin
Crystallography, X-Ray
DNA Damage
DNA Replication
Endosomal Sorting Complexes Required for Transport
Genetic Predisposition to Disease
Genomic Instability
Humans
Mitosis
Neoplasms
Phosphorylation
Polymorphism, Genetic
RNA, Small Interfering
Tumor Suppressor Protein p53