DSS1 is required for proper Integrator–PP2A function

Congling Xu (), Qian-Xing Zhou, Hai Zheng, Aixia Song, Wen-Ying Zhao, Ting-Ting Xu, Yan Xiong, Yi-Jie Zhang, Zixuan Huang, Yanhui Xu (), Jingdong Cheng () and Fei Xavier Chen ()
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Congling Xu: Tongji University
Qian-Xing Zhou: Fudan University
Hai Zheng: Fudan University
Aixia Song: Fudan University
Wen-Ying Zhao: Tongji University
Ting-Ting Xu: Tongji University
Yan Xiong: Fudan University
Yi-Jie Zhang: Tongji University
Zixuan Huang: Fudan University
Yanhui Xu: Fudan University
Jingdong Cheng: Fudan University
Fei Xavier Chen: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Integrator–PP2A (INTAC) is a highly modular complex orchestrating the transition of paused RNA polymerase II into productive elongation or promoter-proximal premature termination, with its loss resulting in transcription dysregulation and genome instability. Here, we identify human DSS1—a flexible 70-residue protein found in multiple functionally diverse complexes including the 26S proteasome—as an integral subunit of the INTAC backbone. Structural analysis of DSS1–INTAC, both alone and in association with paused polymerase, demonstrates intimate interactions between DSS1 and the INTAC backbone. We identify tryptophan 39 of DSS1 as being critical for interacting with INTAC and find that its mutation disrupts DSS1’s interaction with INTAC, while maintaining DSS1’s interaction with the proteasome. This substitution not only impairs INTAC-dependent transcriptional regulation, but also reveals that INTAC is DSS1’s major chromatin-bound form. Together, our findings reveal a role for DSS1 in supporting the structure and regulatory functions of INTAC.

Date: 2025
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DOI: 10.1038/s41467-025-61257-4

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