Multiple direct interactions of TBP with the MYC oncoprotein

Transcription factor c-MYC is a potent oncoprotein; however, the mechanism of transcriptional regulation via MYC-protein interactions remains poorly understood. The TATA-binding protein (TBP) is an essential component of the transcription initiation complex TFIID and is required for gene expression. We identify two discrete regions mediating MYC-TBP interactions using structural, biochemical and cellular approaches. A 2.4 -Å resolution crystal structure reveals that human MYC amino acids 98–111 interact with TBP in the presence of the amino-terminal domain 1 of TBP-associated factor 1 (TAF1 TAND1 ). Using biochemical approaches, we have shown that MYC amino acids 115–124 also interact with TBP independently of TAF1 TAND1 . Modeling reveals that this region of MYC resembles a TBP anchor motif found in factors that regulate TBP promoter loading. Site-specific MYC mutants that abrogate MYC-TBP interaction compromise MYC activity. We propose that MYC-TBP interactions propagate transcription by modulating the energetic landscape of transcription initiation complex assembly. Structural, biophysical and modeling approaches, combined with cell-based assays, reveal how the oncogenic transcription factor MYC interacts with subunits of the general transcription factor TFIID to modulate gene expression.