title: Genome-wide map of nuclear protein degradation shows NCoR1 turnover as a key to mitochondrial gene regulation.
abstract: Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: catic@post.harvard.edu.
authors: André
authors: A
authors: Catic
authors: Carol Y
authors: CY
authors: Suh
authors: Cedric T
authors: CT
authors: Hill
authors: Laurence
authors: L
authors: Daheron
authors: Theresa
authors: T
authors: Henkel
authors: Keith W
authors: KW
authors: Orford
authors: David M
authors: DM
authors: Dombkowski
authors: Tao
authors: T
authors: Liu
authors: X Shirley
authors: XS
authors: Liu
authors: David T
authors: DT
authors: Scadden
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D059748:Proteolysis; D050436:Regulatory Elements, Transcriptional; D054875:Ubiquitination
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1