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Mol Cell. 2016 Jan 7;61(1):54-67. doi: 10.1016/j.molcel.2015.11.007. Epub 2015 Dec 10.

Ubiquitin-Dependent Turnover of MYC Antagonizes MYC/PAF1C Complex Accumulation to Drive Transcriptional Elongation.

Author information

1
Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
2
Comprehensive Cancer Center Mainfranken, Versbacher Straße 5, 97078 Würzburg, Germany.
3
Department of Structural Immunology, Institute of Innate Immunity, University Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
4
Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, Versbacher Straße 5, 97078 Würzburg, Germany. Electronic address: martin.eilers@biozentrum.uni-wuerzburg.de.
5
Comprehensive Cancer Center Mainfranken, Versbacher Straße 5, 97078 Würzburg, Germany; Department of Radiation Oncology, University Hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany. Electronic address: nikita.popov@biozentrum.uni-wuerzburg.de.

Abstract

MYC is an unstable protein, and its turnover is controlled by the ubiquitin system. Ubiquitination enhances MYC-dependent transactivation, but the underlying mechanism remains unresolved. Here we show that MYC proteasomal turnover is dispensable for loading of RNA polymerase II (RNAPII). In contrast, MYC turnover is essential for recruitment of TRRAP, histone acetylation, and binding of BRD4 and P-TEFb to target promoters, leading to phosphorylation of RNAPII and transcriptional elongation. In the absence of histone acetylation and P-TEFb recruitment, MYC associates with the PAF1 complex (PAF1C) through a conserved domain in the MYC amino terminus ("MYC box I"). Depletion of the PAF1C subunit CDC73 enhances expression of MYC target genes, suggesting that the MYC/PAF1C complex can inhibit transcription. Because several ubiquitin ligases bind to MYC via the same domain ("MYC box II") that interacts with TRRAP, we propose that degradation of MYC limits the accumulation of MYC/PAF1C complexes during transcriptional activation.

KEYWORDS:

MYC; PAF1C; RNA polymerase; proteasomal degradation; transcriptional elongation; ubiquitin

PMID:
26687678
DOI:
10.1016/j.molcel.2015.11.007
[Indexed for MEDLINE]
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