BRD4-targeting PROTAC as a unique tool to study biomolecular condensates
Abstract Biomolecular condensates play key roles in various biological processes. However, specific condensation modulators are currently lacking. PROTAC is a new technology that can use small molecules to degrade target proteins specifically. PROTAC molecules are expected to regulate biomolecular c...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-05-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00544-0 |
| _version_ | 1797827744325697536 |
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| author | Yi Shi Yuan Liao Qianlong Liu Zhihao Ni Zhenzhen Zhang Minglei Shi Pilong Li Haitao Li Yu Rao |
| author_facet | Yi Shi Yuan Liao Qianlong Liu Zhihao Ni Zhenzhen Zhang Minglei Shi Pilong Li Haitao Li Yu Rao |
| author_sort | Yi Shi |
| collection | DOAJ |
| description | Abstract Biomolecular condensates play key roles in various biological processes. However, specific condensation modulators are currently lacking. PROTAC is a new technology that can use small molecules to degrade target proteins specifically. PROTAC molecules are expected to regulate biomolecular condensates dynamically by degrading/recovering key molecules in biomolecular condensates. In this study, we employed a BRD4-targeting PROTAC molecule to regulate the super-enhancer (SE) condensate and monitored the changes of SE condensate under PROTAC treatment using live-cell imaging and high-throughput sequencing technologies. As a result, we found that BRD4-targeting PROTACs can significantly reduce the BRD4 condensates, and we established a quantitative method for tracking BRD4 condensates by PROTAC and cellular imaging. Surprisingly and encouragingly, BRD4 condensates were observed to preferentially form and play specialized roles in biological process regulation for the first time. Additionally, BRD4 PROTAC makes it possible to observe the dynamics of other condensate components under the continued disruption of BRD4 condensates. Together, these results shed new light on research methods for liquid-liquid phase separation (LLPS), and specifically demonstrate that PROTAC presents a powerful and distinctive tool for the study of biomolecular condensates. |
| first_indexed | 2024-04-09T12:53:16Z |
| format | Article |
| id | doaj.art-e89d9a561dba4389a2c83f8b54b54c6a |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-09T12:53:16Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-e89d9a561dba4389a2c83f8b54b54c6a2023-05-14T11:08:02ZengNature Publishing GroupCell Discovery2056-59682023-05-019111310.1038/s41421-023-00544-0BRD4-targeting PROTAC as a unique tool to study biomolecular condensatesYi Shi0Yuan Liao1Qianlong Liu2Zhihao Ni3Zhenzhen Zhang4Minglei Shi5Pilong Li6Haitao Li7Yu Rao8MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversityMinistry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversityMOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversityMOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversityMinistry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversityMOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic & Systems Biology, BNRist, School of Medicine, Tsinghua UniversityBeijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityMinistry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversityMOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversityAbstract Biomolecular condensates play key roles in various biological processes. However, specific condensation modulators are currently lacking. PROTAC is a new technology that can use small molecules to degrade target proteins specifically. PROTAC molecules are expected to regulate biomolecular condensates dynamically by degrading/recovering key molecules in biomolecular condensates. In this study, we employed a BRD4-targeting PROTAC molecule to regulate the super-enhancer (SE) condensate and monitored the changes of SE condensate under PROTAC treatment using live-cell imaging and high-throughput sequencing technologies. As a result, we found that BRD4-targeting PROTACs can significantly reduce the BRD4 condensates, and we established a quantitative method for tracking BRD4 condensates by PROTAC and cellular imaging. Surprisingly and encouragingly, BRD4 condensates were observed to preferentially form and play specialized roles in biological process regulation for the first time. Additionally, BRD4 PROTAC makes it possible to observe the dynamics of other condensate components under the continued disruption of BRD4 condensates. Together, these results shed new light on research methods for liquid-liquid phase separation (LLPS), and specifically demonstrate that PROTAC presents a powerful and distinctive tool for the study of biomolecular condensates.https://doi.org/10.1038/s41421-023-00544-0 |
| spellingShingle | Yi Shi Yuan Liao Qianlong Liu Zhihao Ni Zhenzhen Zhang Minglei Shi Pilong Li Haitao Li Yu Rao BRD4-targeting PROTAC as a unique tool to study biomolecular condensates Cell Discovery |
| title | BRD4-targeting PROTAC as a unique tool to study biomolecular condensates |
| title_full | BRD4-targeting PROTAC as a unique tool to study biomolecular condensates |
| title_fullStr | BRD4-targeting PROTAC as a unique tool to study biomolecular condensates |
| title_full_unstemmed | BRD4-targeting PROTAC as a unique tool to study biomolecular condensates |
| title_short | BRD4-targeting PROTAC as a unique tool to study biomolecular condensates |
| title_sort | brd4 targeting protac as a unique tool to study biomolecular condensates |
| url | https://doi.org/10.1038/s41421-023-00544-0 |
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