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Structural Basis of DNA-Dependent Coactivator Recruitment by the Tuft Cell Master Regulator POU2F3 [CUT&Run]

GSE302003 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 6 samples Submitted 2026/01/01 Platform GPL30173
Summary
The transcription factor POU2F3 defines the identity of tuft cells and underlies a distinct molecular subtype of small cell lung cancer (SCLC). Although POU2F3 is considered undruggable, its activity critically depends on the coactivators OCA-T1 and OCA-T2. Here, we demonstrate that acute suppression of either POU2F3 or OCA-T1 induces regression of tuft cell-like SCLC xenografts in vivo. To explore the structural basis and druggability of this dependency, we solved crystal structures of POU2F3 bound to OCA-T1 or OCA-T2 in complex with DNA, revealing a tripartite, DNA-dependent interface. We further employed deep mutational scanning to systematically assess the functional impact of 4,218 missense variants in POU2F3 and OCA-T1, uncovering both mutation-sensitive hotspots and structurally constrained regions critical for tumor cell fitness. These findings define a unique transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3–OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.
Published in
Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3
Alpsoy A, Ipsaro JJ, Skopelitis D et al. · Cell reports 2025 · PMID 41260223 · doi:10.1016/j.celrep.2025.116572
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Direct links to NCBI, no account and no request form: the whole study as GSE302003_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 6 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1288268 and SRA study SRP599135. Searching any of these in the dataset finder brings you back here.

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