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

Alpsoy, Aktan, Ipsaro, Jonathan J, Skopelitis, Damianos, Pal, Sujay, Chung, Frank S, Carpenter, Shannon, Desmarais, John J, Wu, Xiaoli S, Chang, Kenneth, DiMare, Matthew T, Harten, Erin, Bergman, Staci, Kinney, Justin B, Engelman, Jeffrey A, Bhang, Hyo-Eun C, Joshua-Tor, Leemor, Vakoc, Christopher R (November 2025) Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3. Cell Reports. p. 116572. ISSN 2211-1247

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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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
Investigative techniques and equipment
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
CSHL labs > Chang lab
CSHL labs > Joshua-Tor lab
CSHL labs > Kinney lab
CSHL labs > Vakoc lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 18 November 2025
Date Deposited: 02 Dec 2025 16:03
Last Modified: 02 Dec 2025 16:03
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42022

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