Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2

Neil Justin, Ying Zhang, Cataldo Tarricone, Stephen R. Martin, Shuyang Chen, Elizabeth Underwood, Valeria De Marco, Lesley F. Haire, Philip A. Walker, Danny Reinberg, Jon R. Wilson and Steven J. Gamblin ()
Additional contact information
Neil Justin: The Francis Crick Institute, Mill Hill Laboratory
Ying Zhang: The Francis Crick Institute, Mill Hill Laboratory
Cataldo Tarricone: The Francis Crick Institute, Mill Hill Laboratory
Stephen R. Martin: Structural Biology Science Technology Platform, Francis Crick Institute, Mill Hill Laboratory
Shuyang Chen: The Francis Crick Institute, Mill Hill Laboratory
Elizabeth Underwood: The Francis Crick Institute, Mill Hill Laboratory
Valeria De Marco: The Francis Crick Institute, Mill Hill Laboratory
Lesley F. Haire: The Francis Crick Institute, Mill Hill Laboratory
Philip A. Walker: Structural Biology Science Technology Platform, Francis Crick Institute, Mill Hill Laboratory
Danny Reinberg: New York University School of Medicine
Jon R. Wilson: The Francis Crick Institute, Mill Hill Laboratory
Steven J. Gamblin: The Francis Crick Institute, Mill Hill Laboratory

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification.

Date: 2016
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/ncomms11316 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11316

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms11316

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().