DSS1 is required for proper Integrator–PP2A function
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 f...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61257-4 |
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| author | 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 Fei Xavier Chen |
| author_facet | 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 Fei Xavier Chen |
| author_sort | Congling Xu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c4137d9c09844fbc9a221f09bd7b3723 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c4137d9c09844fbc9a221f09bd7b37232025-08-20T03:45:35ZengNature PortfolioNature Communications2041-17232025-07-0116111310.1038/s41467-025-61257-4DSS1 is required for proper Integrator–PP2A functionCongling Xu0Qian-Xing Zhou1Hai Zheng2Aixia Song3Wen-Ying Zhao4Ting-Ting Xu5Yan Xiong6Yi-Jie Zhang7Zixuan Huang8Yanhui Xu9Jingdong Cheng10Fei Xavier Chen11Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Life Sciences and Technology, Tongji UniversityFudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Institutes of Biomedical Sciences, Fudan UniversityFudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Institutes of Biomedical Sciences, Fudan UniversityFudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Institutes of Biomedical Sciences, Fudan UniversityShanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Life Sciences and Technology, Tongji UniversityFudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Institutes of Biomedical Sciences, Fudan UniversityShanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Life Sciences and Technology, Tongji UniversityMinhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan UniversityFudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Institutes of Biomedical Sciences, Fudan UniversityMinhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan UniversityFudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Institutes of Biomedical Sciences, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41467-025-61257-4 |
| spellingShingle | 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 Fei Xavier Chen DSS1 is required for proper Integrator–PP2A function Nature Communications |
| title | DSS1 is required for proper Integrator–PP2A function |
| title_full | DSS1 is required for proper Integrator–PP2A function |
| title_fullStr | DSS1 is required for proper Integrator–PP2A function |
| title_full_unstemmed | DSS1 is required for proper Integrator–PP2A function |
| title_short | DSS1 is required for proper Integrator–PP2A function |
| title_sort | dss1 is required for proper integrator pp2a function |
| url | https://doi.org/10.1038/s41467-025-61257-4 |
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