Author(s)
Danny Reinberg
Published 16 Projects
Polycomb Spreading Biochemistry Molecular Biology Nucleation
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Video Abstract (AI generated) (01:32) Paper Preprint Molecular CellPRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit, promoting an allosteric activation of the complex stimulating H3K27me3 deposition on chromatin. Here, we report a step-wise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifest little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we further demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2-Y646X oncogenic mutations. These results revealed critical implications to the regulation and biology of PRC2 and a novel vulnerability of PRC2 in tackling PRC2-addicted cancers.
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Danny Reinberg. (2021, Nov 7).Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin[Video]. Scitok. https://scitok.com/project/p/4e0689c9
Lee Chul-Hwan. "Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin" Scitok, uploaded by Reinberg Danny, 7 Nov, 2021, https://scitok.com/project/p4e0689c9
Danny Reinberg. "Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin" Scitok. (Nov 7, 2021). https://scitok.com/project/p/4e0689c9
Danny Reinberg (Nov 7, 2021). Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin Scitok. https://scitok.com/project/p/4e0689c9
Danny Reinberg. Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin[video]. 2021 Nov 7. https://scitok.com/project/p/4e0689c9
@online{al2006link, title={ Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin }, author={ Reinberg, Danny }, organization={Scitok}, month={ Nov }, day={ 7 }, year={ 2021 }, url = {https://scitok.com/project/p/4e0689c9}, }