Methylation of lysine 27 on histone H3 by the polycomb repressive complex 2 (PRC2) leads to transcriptional repression of genes which are critical to development. PRC2 core complex is composed of the histone methyltransferase EZH2, EED, and SUZ12. Knockdown of any of the PRC2 core subunits results in a concomitant loss of the other subunits which is mediated by the ubiquitin (Ub)-proteasome system (UPS). Inhibition of cellular methyltransferases by 3-deazaneplanocin A (DZNep) also leads to dissociation of the PRC2 complex and rapid degradation of its subunits. Interestingly, the expression of several Ub ligases was induced following DZNep treatment, suggesting that PRC2 might repress the Ub ligase(s) that target its subunits for degradation. Here we confirm that individual PRC2 subunits are ubiquitinated and rapidly degraded by the proteasome. One of the DZNep-induced Ub ligases, PRAJA1, can target PRC2 subunits for proteasomal degradation. PRAJA1 directly ubiquitinates individual PRC2 subunits in a cell free system, which leads to their proteasomal degradation. Expression of PRAJA1 but not of an inactive RING finger mutant of the protein, enhanced the degradation of individual PRC2 subunits in cells. Taken together, our results suggest a role for PRAJA1 in regulating the level of PRC2 by targeting its free subunits for Ub-mediated proteasomal degradation.
|Original language||American English|
|Number of pages||6|
|Journal||Biochemical and Biophysical Research Communications|
|State||Published - 13 May 2011|
Bibliographical noteFunding Information:
We thank Dr. Victor E. Marquez, National Cancer Institute, Frederick, MD, USA, for the generous gift of DZNep. Research in the laboratory of A.C. is supported by grants from the Dr. Miriam and Sheldon Adelson Foundation for Medical Research (AMRF), the Israel Science Foundation (ISF), the German-Israeli Foundation for Research and Scientific Development (GIF), the Deutsch-Israelische Projektkooperation (DIP), and Rubicon, the European Union (EU) Network of Excellence studying the Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation. A.C. is an Israel Cancer Research Fund (ICRF) USA Professor.