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


ABSTRACT: Transcriptional factors ETS1/2 and p52 synergize downstream of non-canonical NF-?B 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 ?B sites on the DNA to function during non-canonical NF-?B 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-?B signaling are not limited to those driven by consensus ?B sequences.

SUBMITTER: Xu X 

PROVIDER: S-EPMC6085347 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Xu Xueyong X   Li Yinghui Y   Bharath Sakshibeedu R SR   Ozturk Mert Burak MB   Bowler Matthew W MW   Loo Bryan Zong Lin BZL   Tergaonkar Vinay V   Song Haiwei H  

Nature communications 20180809 1


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 promote  ...[more]

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