Suppressing Aneuploidy-Associated Phenotypes Improves the Fitness of Trisomy 21 Cells
Williams, Jessica F.
King, Megan C.
Torres, Eduardo M.
UMass Chan AffiliationsDepartment of Molecular, Cell and Cancer Biology
Cell and Developmental Biology
Cellular and Molecular Physiology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Nervous System Diseases
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AbstractAn abnormal number of chromosomes, or aneuploidy, accounts for most spontaneous abortions, causes developmental defects, and is associated with aging and cancer. The molecular mechanisms by which aneuploidy disrupts cellular function remain largely unknown. Here, we show that aneuploidy disrupts the morphology of the nucleus. Mutations that increase the levels of long-chain bases suppress nuclear abnormalities of aneuploid yeast independent of karyotype identity. Quantitative lipidomics indicates that long-chain bases are integral components of the nuclear membrane in yeast. Cells isolated from patients with Down syndrome also show that abnormal nuclear morphologies and increases in long-chain bases not only suppress these abnormalities but also improve their fitness. We obtained similar results with cells isolated from patients with Patau or Edward syndrome, indicating that increases in long-chain bases improve the fitness of aneuploid cells in yeast and humans. Targeting lipid biosynthesis pathways represents an important strategy to suppress nuclear abnormalities in aneuploidy-associated diseases.
Cell Rep. 2019 Nov 19;29(8):2473-2488.e5. doi: 10.1016/j.celrep.2019.10.059. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41258
RightsCopyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).