Molecular Cell

, volume 70 , issue 3 , pages 422-434000000

Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin

Chul Hwan Lee ^{1, 2}

Jia Ray Yu ^{1, 2}

S. Kumar ³

Ying Jin ⁴

Gary Leroy ^{1, 2}

Natarajan V. Bhanu ⁵

Syuzo Kaneko ^{1, 2}

Benjamin Garcia ⁵

Andrew J. S. Hamilton ³

Danny Reinberg ^{1, 2}

Hide authors affiliations Show authors affiliations: 5 affiliations

HOWARD HUGHES MEDICAL INSTITUTE |

NEW YORK UNIVERSITY |

Department of Chemistry, New York University, New York, NY, 10003, USA |

⁴

Shared Bioinformatics Core, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA |

⁵

Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. |

Publication type: Journal Article

Publication date: 2018-05-01

Elsevier

Molecular Cell

scimago Q1

wos Q1

SJR: 9.051

CiteScore: 24.4

Impact factor: 16.6

ISSN: 10972765, 10974164

DOI: 10.1016/j.molcel.2018.03.020

Copy DOI

PubMed ID: 29681499

Molecular Biology

Cell Biology

Abstract

PRC2 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. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifested 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 demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2Y646X oncogenic mutations. These results revealed critical implications for the regulation and biology of PRC2 and a vulnerability in tackling PRC2-addicted cancers.

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GOST |

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GOST Copy

Lee C. H. et al. Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin // Molecular Cell. 2018. Vol. 70. No. 3. pp. 422-434000000.

GOST all authors (up to 50) Copy

Lee C. H., Yu J. R., Kumar S., Jin Y., Leroy G., Bhanu N. V., Kaneko S., Garcia B., Hamilton A. J. S., Reinberg D. Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin // Molecular Cell. 2018. Vol. 70. No. 3. pp. 422-434000000.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1016/j.molcel.2018.03.020

UR - https://doi.org/10.1016/j.molcel.2018.03.020

TI - Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin

T2 - Molecular Cell

AU - Lee, Chul Hwan

AU - Yu, Jia Ray

AU - Kumar, S.

AU - Jin, Ying

AU - Leroy, Gary

AU - Bhanu, Natarajan V.

AU - Kaneko, Syuzo

AU - Garcia, Benjamin

AU - Hamilton, Andrew J. S.

AU - Reinberg, Danny

PY - 2018

DA - 2018/05/01

PB - Elsevier

SP - 422-434000000

IS - 3

VL - 70

PMID - 29681499

SN - 1097-2765

SN - 1097-4164

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2018_Lee,

author = {Chul Hwan Lee and Jia Ray Yu and S. Kumar and Ying Jin and Gary Leroy and Natarajan V. Bhanu and Syuzo Kaneko and Benjamin Garcia and Andrew J. S. Hamilton and Danny Reinberg},

title = {Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin},

journal = {Molecular Cell},

year = {2018},

volume = {70},

publisher = {Elsevier},

month = {may},

url = {https://doi.org/10.1016/j.molcel.2018.03.020},

number = {3},

pages = {422--434000000},

doi = {10.1016/j.molcel.2018.03.020}

}

MLA

Cite this

MLA Copy

Lee, Chul Hwan, et al. “Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin.” Molecular Cell, vol. 70, no. 3, May. 2018, pp. 422-434000000. https://doi.org/10.1016/j.molcel.2018.03.020.

Publisher

Elsevier

Journal

Molecular Cell

scimago Q1

wos Q1

SJR

9.051

CiteScore

24.4

Impact factor

16.6

ISSN

10972765 (Print)

10974164 (Electronic)