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

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 Fekkes, Baudouin Gerard, Craig Karr, Manav Korpal, Xiang Liu, Jason T. Lowe, Yoshiharu Mizui, James Palacino, Eunice Park, Peter G. Smith, Vanitha Subramanian, Zhenhua Jeremy Wu, Jian Zou, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen () and Ping Zhu ()
Additional contact information
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

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15522

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