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TitleStructural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation.
Journal, issue, pagesJ Am Chem Soc, Vol. 145, Issue 12, Page 6811-6822, Year 2023
Publish dateMar 29, 2023
AuthorsZhipeng A Wang / Jonathan W Markert / Samuel D Whedon / Maheeshi Yapa Abeywardana / Kwangwoon Lee / Hanjie Jiang / Carolay Suarez / Hening Lin / Lucas Farnung / Philip A Cole /
PubMed AbstractThe reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins ...The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins are a family of NAD-dependent HDAC enzymes, and one member, sirtuin 6 (Sirt6), influences DNA repair, transcription, and aging. Here, we demonstrate that Sirt6 is efficient at deacetylating several histone H3 acetylation sites, including its canonical site Lys9, in the context of nucleosomes but not free acetylated histone H3 protein substrates. By installing a chemical warhead at the Lys9 position of histone H3, we trap a catalytically poised Sirt6 in complex with a nucleosome and employ this in cryo-EM structural analysis. The structure of Sirt6 bound to a nucleosome reveals extensive interactions between distinct segments of Sirt6 and the H2A/H2B acidic patch and nucleosomal DNA, which accounts for the rapid deacetylation of nucleosomal H3 sites and the disfavoring of histone H2B acetylation sites. These findings provide a new framework for understanding how HDACs target and regulate chromatin.
External linksJ Am Chem Soc / PubMed:36930461 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

EMDB-28915, PDB-8f86:
SIRT6 bound to an H3K9Ac nucleosome
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-ZSL:
[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl [(3aR,5R,6R,6aR)-6-hydroxytetrahydro-2H-furo[2,3-d][1,3]oxathiol-5-yl]methyl dihydrogen diphosphate (non-preferred name)

ChemComp-ZN:
Unknown entry

Source
  • xenopus laevis (African clawed frog)
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsGENE REGULATION / nucleosome / SIRTUIN6 / histone deacylation / H3K9Ac

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