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

Jessica B.A. Sadler, Dawn M. Wenzel, Lauren K. Williams, Marta Guindo-Martínez, Steven L. Alam, Josep M. Mercader, David Torrents, Katharine S Ullman, Wesley I Sundquist, Juan Martin-Serrano

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
PagesE8900-E8908
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number38
DOIs
StatePublished - Sep 18 2018

Fingerprint

Endosomal Sorting Complexes Required for Transport
Multivesicular Bodies
Genomic Instability
M Phase Cell Cycle Checkpoints
Neoplasms
Proteins
Cell Separation
DNA Replication
Oncogenes
DNA Damage
Chromatin
Carcinogenesis
Chromosomes
Alleles

Keywords

  • Abscission checkpoint
  • Cancer
  • CHMP4C
  • ESCRT pathway
  • Genome instability

ASJC Scopus subject areas

  • General

Cite this

Sadler, J. B. A., Wenzel, D. M., Williams, L. K., Guindo-Martínez, M., Alam, S. L., Mercader, J. M., ... Martin-Serrano, J. (2018). A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability. Proceedings of the National Academy of Sciences of the United States of America, 115(38), E8900-E8908. https://doi.org/10.1073/pnas.1805504115

A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability. / Sadler, Jessica B.A.; Wenzel, Dawn M.; Williams, Lauren K.; Guindo-Martínez, Marta; Alam, Steven L.; Mercader, Josep M.; Torrents, David; Ullman, Katharine S; Sundquist, Wesley I; Martin-Serrano, Juan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 38, 18.09.2018, p. E8900-E8908.

Research output: Contribution to journalArticle

Sadler, Jessica B.A. ; Wenzel, Dawn M. ; Williams, Lauren K. ; Guindo-Martínez, Marta ; Alam, Steven L. ; Mercader, Josep M. ; Torrents, David ; Ullman, Katharine S ; Sundquist, Wesley I ; Martin-Serrano, Juan. / A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 38. pp. E8900-E8908.
@article{4eadcd4d4fd0463e839bc6ba8f89aeb5,
title = "A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability",
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 = "Abscission checkpoint, Cancer, CHMP4C, ESCRT pathway, Genome instability",
author = "Sadler, {Jessica B.A.} and Wenzel, {Dawn M.} and Williams, {Lauren K.} and Marta Guindo-Mart{\'i}nez and Alam, {Steven L.} and Mercader, {Josep M.} and David Torrents and Ullman, {Katharine S} and Sundquist, {Wesley I} and Juan Martin-Serrano",
year = "2018",
month = "9",
day = "18",
doi = "10.1073/pnas.1805504115",
language = "English (US)",
volume = "115",
pages = "E8900--E8908",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "38",

}

TY - JOUR

T1 - A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability

AU - Sadler, Jessica B.A.

AU - Wenzel, Dawn M.

AU - Williams, Lauren K.

AU - Guindo-Martínez, Marta

AU - Alam, Steven L.

AU - Mercader, Josep M.

AU - Torrents, David

AU - Ullman, Katharine S

AU - Sundquist, Wesley I

AU - Martin-Serrano, Juan

PY - 2018/9/18

Y1 - 2018/9/18

N2 - 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.

AB - 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.

KW - Abscission checkpoint

KW - Cancer

KW - CHMP4C

KW - ESCRT pathway

KW - Genome instability

UR - http://www.scopus.com/inward/record.url?scp=85053465437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053465437&partnerID=8YFLogxK

U2 - 10.1073/pnas.1805504115

DO - 10.1073/pnas.1805504115

M3 - Article

VL - 115

SP - E8900-E8908

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -