Chemical inhibition of NAT10 corrects defects of laminopathic cells.
American Association for the Advancement of Science
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Larrieu, D., Britton, S., Demir, M., Rodriguez, R., & Jackson, S. (2014). Chemical inhibition of NAT10 corrects defects of laminopathic cells.. Science, 344 (6183), 527-532. https://doi.org/10.1126/science.1252651
Down-regulation and mutations of the nuclear-architecture proteins lamin A and C cause misshapen nuclei and altered chromatin organization associated with cancer and laminopathies, including the premature-aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here, we identified the small molecule "Remodelin" that improved nuclear architecture, chromatin organization, and fitness of both human lamin A/C-depleted cells and HGPS-derived patient cells and decreased markers of DNA damage in these cells. Using a combination of chemical, cellular, and genetic approaches, we identified the acetyl-transferase protein NAT10 as the target of Remodelin that mediated nuclear shape rescue in laminopathic cells via microtubule reorganization. These findings provide insights into how NAT10 affects nuclear architecture and suggest alternative strategies for treating laminopathies and aging.
Cell Line, Tumor, Cell Nucleus, Chromatin, Enzyme Inhibitors, Humans, Hydrazones, Lamin Type A, Microtubules, N-Terminal Acetyltransferase E, Nocodazole, Progeria, Protein Structure, Tertiary, RNA, Small Interfering, Thiazoles
We thank Imagif and Institut de Chimie des Substances Naturelles, centre de recherche CNRS de Gif-sur-Yvette, France, for proteomic analysis. Research in the Jackson laboratory is funded by Cancer Research UK program grant 11 C6/A11224, the European Research Council, and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010-259893 (DDR). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. D.L is funded by an EMBO Long-term fellowship ALTF 834-2011 and by a Project Grant from the Medical Research Council, UK MR/L019116/1, S.B. was funded by an EMBO Long-Term fellowship ALTF 93-2010 and Cancer Research UK. R.R. is supported by the Centre National de la Recherche Scientifique. M.D. is supported by the European Research Council grant DDREAM. T
Cancer Research UK (11224)
Cancer Research UK (18796)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1126/science.1252651
This record's URL: https://www.repository.cam.ac.uk/handle/1810/295202