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TitleNucleosome and ubiquitin position Set2 to methylate H3K36.
Journal, issue, pagesNat Commun, Vol. 10, Issue 1, Page 3795, Year 2019
Publish dateAug 22, 2019
AuthorsSilvija Bilokapic / Mario Halic /
PubMed AbstractHistone H3 lysine 36 methylation (H3K36me) is a conserved histone modification deposited by the Set2 methyltransferases. Recent findings show that over-expression or mutation of Set2 enzymes promotes ...Histone H3 lysine 36 methylation (H3K36me) is a conserved histone modification deposited by the Set2 methyltransferases. Recent findings show that over-expression or mutation of Set2 enzymes promotes cancer progression, however, mechanisms of H3K36me are poorly understood. Set2 enzymes show spurious activity on histones and histone tails, and it is unknown how they obtain specificity to methylate H3K36 on the nucleosome. In this study, we present 3.8 Å cryo-EM structure of Set2 bound to the mimic of H2B ubiquitinated nucleosome. Our structure shows that Set2 makes extensive interactions with the H3 αN, the H3 tail, the H2A C-terminal tail and stabilizes DNA in the unwrapped conformation, which positions Set2 to specifically methylate H3K36. Moreover, we show that ubiquitin contributes to Set2 positioning on the nucleosome and stimulates the methyltransferase activity. Notably, our structure uncovers interfaces that can be targeted by small molecules for development of future cancer therapies.
External linksNat Commun / PubMed:31439846 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 4.1 Å
Structure data

EMDB-0559, PDB-6nzo:
Set2 bound to nucleosome
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-20516, PDB-6px1:
Set2 bound to nucleosome
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-20517, PDB-6px3:
Set2 bound to nucleosome
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • Chaetomium thermophilum (fungus)
  • synthetic construct (others)
  • xenopus laevis (African clawed frog)
  • chaetomium thermophilum (strain dsm 1495 / cbs 144.50 / imi 039719) (fungus)
  • saccharomyces cerevisiae (strain atcc 204508 / s288c) (yeast)
KeywordsGENE REGULATION / Set2 / nucleosome / chromatin / KMT

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