TY - JOUR
T1 - RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2
AU - Zhang, Qi
AU - McKenzie, Nicholas J.
AU - Warneford-Thomson, Robert
AU - Gail, Emma H.
AU - Flanigan, Sarena F.
AU - Owen, Brady M.
AU - Lauman, Richard
AU - Levina, Vitalina
AU - Garcia, Benjamin A.
AU - Schittenhelm, Ralf B.
AU - Bonasio, Roberto
AU - Davidovich, Chen
N1 - Funding Information:
We would like to thank the Monash Biomedical Proteomics Facility for providing instrumentation and technical support. Q.Z. holds an Australian Research Council (ARC) Discovery Early Career Researcher Award (no. DE180100219). N.J.M. is the Isabella and Marcus Foundation Charlee Ferrar Scholar and is also supported through an Australian Government Research Training Program (RTP) Scholarship. R.W.-T. was supported by NIH training grant no. T32GM008216. E.H.G. holds a Biomedicine Discovery Scholarship and is an EMBL-Australia PhD student. B.M.O. is supported through an Australian Government RTP Scholarship and also by the Monash Graduate Excellence Scholarship. R.B. acknowledges support from the NIH (grant no. R01GM127408) and the March of Dimes Foundation (grant no. 1-FY-15–344). C.D. is an EMBL-Australia Group Leader and acknowledges support from the ARC (grant no. DP190103407) and the NHMRC (grant no. APP1162921).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.
AB - Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.
UR - http://www.scopus.com/inward/record.url?scp=85062586511&partnerID=8YFLogxK
U2 - 10.1038/s41594-019-0197-y
DO - 10.1038/s41594-019-0197-y
M3 - Article
C2 - 30833789
AN - SCOPUS:85062586511
SN - 1545-9993
VL - 26
SP - 237
EP - 247
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 3
ER -