title: CCR4/NOT complex associates with the proteasome and regulates histone methylation.
abstract: The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.
authors: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: R Nicholas
authors: RN
authors: Laribee
authors: Yoichiro
authors: Y
authors: Shibata
authors: Douglas P
authors: DP
authors: Mersman
authors: Sean R
authors: SR
authors: Collins
authors: Patrick
authors: P
authors: Kemmeren
authors: Assen
authors: A
authors: Roguev
authors: Jonathan S
authors: JS
authors: Weissman
authors: Scott D
authors: SD
authors: Briggs
authors: Nevan J
authors: NJ
authors: Krogan
authors: Brian D
authors: BD
authors: Strahl
mesh_terms: D002874:Chromosome Mapping; D015825:Chromosomes, Fungal; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000032:analysis / Q000378:metabolism*; D008745:Methylation; D008957:Models, Genetic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae; C501306:Ubc4 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; C086923:MOT2 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; C078657:CCR4 protein, S cerevisiae; D012260:Ribonucleases; D046988:Proteasome Endopeptidase Complex; C092477:PMA1 protein, S cerevisiae; D006180:Proton-Translocating ATPases