5ZMC

Structural Basis for Reactivation of -146C>T Mutant TERT Promoter by cooperative binding of p52 and ETS1/2

Summary for 5ZMC

• Entry DOI: 10.2210/pdb5zmc/pdb
• Descriptor: DNA (5'-D(P*CP*GP*GP*GP*GP*AP*CP*CP*CP*GP*GP*AP*AP*GP*GP*G)-3'), DNA (5'-D(P*GP*CP*CP*CP*TP*TP*CP*CP*GP*GP*GP*TP*CP*CP*CP*C)-3'), Protein C-ets-1, ... (4 entities in total)
• Functional Keywords: ets1, p52, transcription factor, transcription, -146c>t mutant tert promoter activation, transcription-dna complex, transcription/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 56082.24

Authors

Xu, X.,Bharath, S.R.,Song, H. (deposition date: 2018-04-02, release date: 2018-09-19, Last modification date: 2023-11-22)

Primary citation

Xu, X.,Li, Y.,Bharath, S.R.,Ozturk, M.B.,Bowler, M.W.,Loo, B.Z.L.,Tergaonkar, V.,Song, H.
Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1.
Nat Commun, 9:3183-3183, 2018

PubMed Abstract: Transcriptional factors ETS1/2 and p52 synergize downstream of non-canonical NF-κB signaling to drive reactivation of the -146C>T mutant TERT promoter in multiple cancer types, but the mechanism underlying this cooperativity remains unknown. Here we report the crystal structure of a ternary p52/ETS1/-146C>T TERT promoter complex. While p52 needs to associate with consensus κB sites on the DNA to function during non-canonical NF-κB signaling, we show that p52 can activate the -146C>T TERT promoter without binding DNA. Instead, p52 interacts with ETS1 to form a heterotetramer, counteracting autoinhibition of ETS1. Analogous to observations with the GABPA/GABPB heterotetramer, the native flanking ETS motifs are required for sustained activation of the -146C>T TERT promoter by the p52/ETS1 heterotetramer. These observations provide a unifying mechanism for transcriptional activation by GABP and ETS1, and suggest that genome-wide targets of non-canonical NF-κB signaling are not limited to those driven by consensus κB sequences.

PubMed: 30093619
DOI: 10.1038/s41467-018-05644-0

Experimental method

X-RAY DIFFRACTION (2.99 Å)