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 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.
The Wellcome Trust/Cancer Research UK (CRUK) Gurdon Institute and Department of Biochemistry, University of Cambridge, CB2 1QN Cambridge, UK.
Delphine
D
Larrieu
Sébastien
S
Britton
Mukerrem
M
Demir
Raphaël
R
Rodriguez
Stephen P
SP
Jackson
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D002843:Chromatin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D034904:Lamin Type A / Q000235:genetics; D008870:Microtubules / Q000378:metabolism; D063213:N-Terminal Acetyltransferase E / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D063206:N-Terminal Acetyltransferases; D015739:Nocodazole / Q000494:pharmacology; D011371:Progeria / Q000201:enzymology* / Q000235:genetics; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
C000588556:4-(4-cyanophenyl)-2-(2-cyclopentylidenehydrazinyl)thiazole; D002843:Chromatin; D004791:Enzyme Inhibitors; D006835:Hydrazones; D034904:Lamin Type A; D034741:RNA, Small Interfering; D013844:Thiazoles; C440308:lamin C; D063213:N-Terminal Acetyltransferase E; D063206:N-Terminal Acetyltransferases; C522989:NAT10 protein, human; D015739:Nocodazole