Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
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Date
2018
Authors
Xu, X.
Li, Y.
Bharath, S.R.
Ozturk, M.B.
Bowler, M.W.
Loo, B.Z.L.
Tergaonkar, V.
Song, H.
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Journal article
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Nature Communications, 2018; 9(1, article no. 3183):1-10
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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.
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Data source: Supporting information, https://doi.org/10.1038/s41467-018-05644-0
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Copyright 2018 The Author(s)