Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3

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 determine crystal structures of POU2F3 bound to OCA-T1 or OCA-T2 in complex with DNA, revealing a tripartite, DNA-dependent interface. We further employ deep mutational scanning to 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 transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3-OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.

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Publication Details

Journal
Cell Reports
Published
2025-11-01
DOI
https://doi.org/10.1016/j.celrep.2025.116572
Citations
1
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
1.05

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article

Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3

Jonathan J. Ipsaro, Christopher R. Vakoc, Sujay Pal, Fung‐Lung Chung et al.
1 citations
Cell Reports
Lung Cancer Research Studies
1.05
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Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3

Jonathan J. Ipsaro, Christopher R. Vakoc, Sujay Pal, Fung‐Lung Chung, Jeffrey A. Engelman, Damianos Skopelitis, Shana Bergman, John J. Desmarais, Kenneth Chang, Aktan Alpsoy, Justin B. Kinney, Shannon L. Carpenter, Matthew T. DiMare, Leemor Joshua‐Tor, Xiaoli Wu, Hyo‐eun C. Bhang, Erin Harten
article en
1 citations

Abstract

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 determine crystal structures of POU2F3 bound to OCA-T1 or OCA-T2 in complex with DNA, revealing a tripartite, DNA-dependent interface. We further employ deep mutational scanning to 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 transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3-OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.

Cell ReportsVol. 44(11)
Cold Spring Harbor Laboratory (US), Selecta Biosciences (United States) (US)
U.S. Department of Defense, Pershing Square Sohn Cancer Research Alliance, Northwell Health, National Institutes of Health, National Cancer Institute
Openalex Percentile: Top 16%
Lung Cancer Research Studies
1.05
DOIOpen Access PDFOpenAlex
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