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

Autor:	Sadler JBA; Department of Infectious Diseases, Faculty of Life Sciences and Medicine, King's College London, SE1 9RT London, United Kingdom., Wenzel DM; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112., Strohacker LK; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112., Guindo-Martínez M; Joint Barcelona Supercomputing Center-Centre for Genomic Regulation-Institute for Research in Biomedicine Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain., Alam SL; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112., Mercader JM; Joint Barcelona Supercomputing Center-Centre for Genomic Regulation-Institute for Research in Biomedicine Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain.; Program in Metabolism, Broad Institute of Harvard and MIT, Cambridge, MA 02142.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142.; Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114., Torrents D; Joint Barcelona Supercomputing Center-Centre for Genomic Regulation-Institute for Research in Biomedicine Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain., Ullman KS; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112., Sundquist WI; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112; wes@biochem.utah.edu juan.martin_serrano@kcl.ac.uk., Martin-Serrano J; 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.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Sep 18; Vol. 115 (38), pp. E8900-E8908. Date of Electronic Publication: 2018 Sep 04.
DOI:	10.1073/pnas.1805504115
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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