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

Area of Science:

• Molecular Biology
• Cancer Biology
• Structural Biology

Background:

• Non-canonical NF-κB signaling activates the mutant TERT promoter via ETS1/2 and p52 transcription factors.
• The precise mechanism of ETS1/p52 cooperativity in TERT promoter activation is not understood.

Purpose of the Study:

• To elucidate the mechanism of ETS1/p52 cooperativity in activating the -146C>T mutant TERT promoter.
• To determine the structural basis for this transcriptional activation.

Main Methods:

• X-ray crystallography to determine the structure of the p52/ETS1/TERT promoter complex.
• Functional assays to assess the role of DNA binding and protein-protein interactions.

Main Results:

• The crystal structure revealed a ternary complex of p52, ETS1, and the mutant TERT promoter.
• p52 activates the promoter independently of DNA binding by interacting with ETS1.
• This interaction forms a heterotetramer that counteracts ETS1 autoinhibition, requiring flanking ETS motifs for sustained activation.

Conclusions:

• A novel mechanism for TERT promoter activation by p52/ETS1 heterotetramer formation is proposed.
• This mechanism provides insights into transcriptional regulation by non-canonical NF-κB signaling beyond consensus κB sites.
• Findings suggest broader implications for understanding genome-wide targets of non-canonical NF-κB signaling.