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. doi: 10.1073/pnas.1805504115. Epub 2018 Sep 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Chromatin
  • Endosomal Sorting Complexes Required for Transport
  • PDCD6IP protein, human
  • RNA, Small Interfering
  • Snf7-3 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53

Associated data

  • PDB/5V3R
  • PDB/5WA1