Pseudouridylation of 7SK by PUS7 regulates Pol II transcription elongation

Yutao Zhao, Hui-Lung Sun, Wenlong Li, Chang Ye, Xiaoyang Dou, Yong Peng, Tong Wu, Pingluan Wang, Cheng-Wei Ju, Shun Liu, Yuhao Zhong, Qing Dai, Kinga Pajdzik and Chuan He ()
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Yutao Zhao: The University of Chicago
Hui-Lung Sun: The University of Chicago
Wenlong Li: The University of Chicago
Chang Ye: The University of Chicago
Xiaoyang Dou: The University of Chicago
Yong Peng: The University of Chicago
Tong Wu: The University of Chicago
Pingluan Wang: The University of Chicago
Cheng-Wei Ju: The University of Chicago
Shun Liu: The University of Chicago
Yuhao Zhong: The University of Chicago
Qing Dai: The University of Chicago
Kinga Pajdzik: The University of Chicago
Chuan He: The University of Chicago

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Pseudouridine (Ψ) is a widespread RNA modification in various RNA species, including rRNA, tRNA, snRNA and mRNA. Ψ plays a crucial role in RNA metabolism, where it regulates pre-mRNA splicing and affects protein translation. Whether and how Ψ may regulate transcription have not been adequately studied. Here, we report that pseudouridine synthase 7 (PUS7) can mediate pseudouridylation of 7SK small nuclear RNA (snRNA), a regulator of RNA polymerase II (Pol II) promoter-proximal pausing. PUS7 loss leads to hypo-pseudouridylation of 7SK, which promotes dissociation of the positive transcription elongation factor b (P-TEFb) complex from 7SK. The release of P-TEFb from 7SK increases serine 2 phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and enhances transcription elongation. In colorectal cancer (CRC) cells, the Ψ level of 7SK can be modulated by PUS7, or by site-specifically targeted pseudouridylation through dCas13b-guided system. Hypo-pseudouridylation on 7SK upon PUS7 depletion promotes KLF6/DDIT3-mediated cell apoptosis and sensitizes CRC cells to 5-FU.

Date: 2025
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DOI: 10.1038/s41467-025-64668-5

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