title: PRAJA1 is a ubiquitin ligase for the polycomb repressive complex 2 proteins.
abstract: 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.
authors.affiliation: Center for Vascular and Tumor Biology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zoabi
authors.forename: Ronen
authors.initials: R
authors.lastname: Sadeh
authors.forename: Prim
authors.initials: P
authors.lastname: de Bie
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C048460:3-deazaneplanocin; D011496:Protein Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C484661:PJA1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000241:Adenosine