1. Academic Validation
  2. Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase

Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase

  • Science. 2020 Nov 27;370(6520):eabb5872. doi: 10.1126/science.abb5872.
Hai Zheng  # 1 2 Yilun Qi  # 1 Shibin Hu  # 1 Xuan Cao  # 3 Congling Xu  # 1 Zhinang Yin 4 Xizi Chen 1 Yan Li 1 Weida Liu 1 Jie Li 1 Jiawei Wang 5 Gang Wei 3 Kaiwei Liang 4 Fei Xavier Chen 6 Yanhui Xu 6 2 7
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai 200032, China.
  • 2 The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, China, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
  • 3 CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 4 Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 5 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 6 Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai 200032, China. feixchen@fudan.edu.cn xuyh@fudan.edu.cn.
  • 7 Human Phenome Institute, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
  • # Contributed equally.
Abstract

The 14-subunit metazoan-specific Integrator contains an Endonuclease that cleaves nascent RNA transcripts. Here, we identified a complex containing Integrator and protein Phosphatase 2A core enzyme (PP2A-AC), termed INTAC. The 3.5-angstrom-resolution structure reveals that nine human Integrator subunits and PP2A-AC assemble into a cruciform-shaped central scaffold formed by the backbone and shoulder modules, with the Phosphatase and Endonuclease modules flanking the opposite sides. As a noncanonical PP2A holoenzyme, the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7 and thus regulates transcription. Our study extends the function of PP2A to transcriptional regulation and reveals how dual enzymatic activities-RNA cleavage and RNA polymerase II dephosphorylation-are structurally and functionally integrated into the INTAC complex.

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