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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Proliferation
  • Chromatin Assembly and Disassembly
  • HEK293 Cells
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Multiprotein Complexes
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Positive Transcriptional Elongation Factor B / metabolism
  • Promoter Regions, Genetic
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • RNA Polymerase II / metabolism
  • Time Factors
  • Transcription Elongation, Genetic*
  • Transcription Factors / metabolism
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination*


  • Adaptor Proteins, Signal Transducing
  • BRD4 protein, human
  • CDC73 protein, human
  • CTR9 protein, human
  • Cell Cycle Proteins
  • Histones
  • MYC protein, human
  • Multiprotein Complexes
  • Nuclear Proteins
  • PAF1 protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Tumor Suppressor Proteins
  • transformation-transcription domain-associated protein
  • Positive Transcriptional Elongation Factor B
  • RNA Polymerase II