Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1

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Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
Title:
Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
Journal Title:
Nature Communications
Keywords:
Publication Date:
09 August 2018
Citation:
Xu, X., Li, Y., Bharath, S.R. et al. Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1. Nat Commun 9, 3183 (2018). https://doi.org/10.1038/s41467-018-05644-0
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work was financially supported by the Agency for Science, Technology and Research and Singapore National Research Foundation under its Competitive Research Programme (NRF-CRP17-2017-02) in Singapore.
Description:
ISSN:
2041-1723
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