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Inositol hexakisphosphate is required for Integrator function

Author

Listed:
  • Min-Han Lin

    (Columbia University)

  • Madeline K. Jensen

    (The University of Texas Medical Branch
    University of Rochester School of Medicine and Dentistry)

  • Nathan D. Elrod

    (The University of Texas Medical Branch)

  • Kai-Lieh Huang

    (The University of Texas Medical Branch
    University of Rochester School of Medicine and Dentistry)

  • Kevin A. Welle

    (University of Rochester School of Medicine and Dentistry)

  • Eric J. Wagner

    (The University of Texas Medical Branch
    University of Rochester School of Medicine and Dentistry)

  • Liang Tong

    (Columbia University)

Abstract

Integrator is a multi-subunit protein complex associated with RNA polymerase II (Pol II), with critical roles in noncoding RNA 3′-end processing and transcription attenuation of a broad collection of mRNAs. IntS11 is the endonuclease for RNA cleavage, as a part of the IntS4-IntS9-IntS11 Integrator cleavage module (ICM). Here we report a cryo-EM structure of the Drosophila ICM, at 2.74 Å resolution, revealing stable association of an inositol hexakisphosphate (IP6) molecule. The IP6 binding site is located in a highly electropositive pocket at an interface among all three subunits of ICM, 55 Å away from the IntS11 active site and generally conserved in other ICMs. We also confirmed IP6 association with the same site in human ICM. IP6 binding is not detected in ICM samples harboring mutations in this binding site. Such mutations or disruption of IP6 biosynthesis significantly reduced Integrator function in snRNA 3′-end processing and mRNA transcription attenuation. Our structural and functional studies reveal that IP6 is required for Integrator function in Drosophila, humans, and likely other organisms.

Suggested Citation

  • Min-Han Lin & Madeline K. Jensen & Nathan D. Elrod & Kai-Lieh Huang & Kevin A. Welle & Eric J. Wagner & Liang Tong, 2022. "Inositol hexakisphosphate is required for Integrator function," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33506-3
    DOI: 10.1038/s41467-022-33506-3
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    References listed on IDEAS

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    1. Sebastian M. Fica & Chris Oubridge & Wojciech P. Galej & Max E. Wilkinson & Xiao-Chen Bai & Andrew J. Newman & Kiyoshi Nagai, 2017. "Structure of a spliceosome remodelled for exon ligation," Nature, Nature, vol. 542(7641), pages 377-380, February.
    2. Quentin Angelo Thomas & Ryan Ard & Jinghan Liu & Bingnan Li & Jingwen Wang & Vicent Pelechano & Sebastian Marquardt, 2020. "Transcript isoform sequencing reveals widespread promoter-proximal transcriptional termination in Arabidopsis," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Corey R. Mandel & Syuzo Kaneko & Hailong Zhang & Damara Gebauer & Vasupradha Vethantham & James L. Manley & Liang Tong, 2006. "Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease," Nature, Nature, vol. 444(7121), pages 953-956, December.
    4. Kevin Sabath & Melanie L. Stäubli & Sabrina Marti & Alexander Leitner & Murielle Moes & Stefanie Jonas, 2020. "INTS10–INTS13–INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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