Chemical Inhibition of NAT10 Corrects Defects of Laminopathic Cells

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 molecu...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2014-05, Vol.344 (6183), p.527-532
Main Authors: Larrieu, Delphine, Britton, Sébastien, Demir, Mukerrem, Rodriguez, Raphaël, Jackson, Stephen P.
Format: Article
Language:English
Subjects:
Cell growth
Cell Line, Tumor
Cell lines
Cell nucleus
Cell Nucleus - drug effects
Cell Nucleus - genetics
Cell Nucleus - ultrastructure
Cellular biology
Cellular senescence
Chemical Sciences
Chromatin
Chromatin - metabolism
DNA damage
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Hydrazones - chemistry
Hydrazones - pharmacology
Lamin Type A - genetics
Lamins
Microtubules
Microtubules - metabolism
Molecular chemistry
Molecules
Mutation
N-Terminal Acetyltransferase E - antagonists & inhibitors
N-Terminal Acetyltransferase E - chemistry
N-Terminal Acetyltransferase E - genetics
N-Terminal Acetyltransferases
Nocodazole - pharmacology
Organic chemistry
Pathology
Progeria - enzymology
Progeria - genetics
Protein Structure, Tertiary
Proteins
Quantification
RNA, Small Interfering - genetics
Thiazoles - chemistry
Thiazoles - pharmacology
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Description
Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1252651