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Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A–SF3b complex

Author

Listed:
  • Teng Teng

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Jennifer HC Tsai

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Xiaoling Puyang

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Michael Seiler

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Shouyong Peng

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Sudeep Prajapati

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Daniel Aird

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Silvia Buonamici

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Benjamin Caleb

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Betty Chan

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Laura Corson

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Jacob Feala

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Peter Fekkes

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Baudouin Gerard

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Craig Karr

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Manav Korpal

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Xiang Liu

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Jason T. Lowe

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Yoshiharu Mizui

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • James Palacino

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Eunice Park

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Peter G. Smith

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Vanitha Subramanian

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Zhenhua Jeremy Wu

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Jian Zou

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Lihua Yu

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Agustin Chicas

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Markus Warmuth

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Nicholas Larsen

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

  • Ping Zhu

    (H3 Biomedicine Inc., 300 Technology Sq, 5th Floor, Cambridge, Massachusetts 02139, USA)

Abstract

Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons. We determine the crystal structure of human PHF5A demonstrating that Y36 is located on a highly conserved surface. Analysis of the cryo-EM spliceosome Bact complex shows that the resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting a competitive mode of action. Collectively, we propose that PHF5A–SF3B1 forms a central node for binding to these splicing modulators.

Suggested Citation

  • Teng Teng & Jennifer HC Tsai & Xiaoling Puyang & Michael Seiler & Shouyong Peng & Sudeep Prajapati & Daniel Aird & Silvia Buonamici & Benjamin Caleb & Betty Chan & Laura Corson & Jacob Feala & Peter F, 2017. "Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A–SF3b complex," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15522
    DOI: 10.1038/ncomms15522
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    Cited by:

    1. Mai Abdel Mouti & Siwei Deng & Martin Pook & Jessica Malzahn & Aniko Rendek & Stefania Militi & Reshma Nibhani & Zahir Soonawalla & Udo Oppermann & Chang-il Hwang & Siim Pauklin, 2023. "KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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