2. Academic Validation
  3. BRD4-targeting PROTAC as a unique tool to study biomolecular condensates

BRD4-targeting PROTAC as a unique tool to study biomolecular condensates

  • Cell Discov. 2023 May 9;9(1):47. doi: 10.1038/s41421-023-00544-0.
Yi Shi # 1 2,  Yuan Liao # 3 4,  Qianlong Liu 1 2,  Zhihao Ni 1,  Zhenzhen Zhang 3,  Minglei Shi 5,  Pilong Li 6,  Haitao Li 7,  Yu Rao 8
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
  • 2 Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China.
  • 3 Ministry 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 University, Beijing, China.
  • 4 Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Beijing, China.
  • 5 MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic & Systems Biology, BNRist, School of Medicine, Tsinghua University, Beijing, China.
  • 6 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. [email protected].
  • 7 Ministry 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 University, Beijing, China. [email protected].
  • 8 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 37156794 DOI: 10.1038/s41421-023-00544-0
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.

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