Characterization of the SF3B1–SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing
- Jian Zhang1,5,
- Jindou Xie2,3,5,
- Ji Huang1,
- Xiangyang Liu1,
- Ruihong Xu2,3,
- Jonas Tholen4,
- Wojciech P. Galej4,
- Liang Tong1,
- James L. Manley1,6 and
- Zhaoqi Liu2,3,6
- 1Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
- 2CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China;
- 3University of Chinese Academy of Sciences, Beijing 100049, China;
- 4European Molecular Biology Laboratory, 38042 Grenoble, France
- Corresponding authors: jlm2{at}columbia.edu, liuzq{at}big.ac.cn
Abstract
The spliceosomal gene SF3B1 is frequently mutated in cancer. While it is known that SF3B1 hotspot mutations lead to loss of splicing factor SUGP1 from spliceosomes, the cancer-relevant SF3B1–SUGP1 interaction has not been characterized. To address this issue, we show by structural modeling that two regions flanking the SUGP1 G-patch make numerous contacts with the region of SF3B1 harboring hotspot mutations. Experiments confirmed that all the cancer-associated mutations in these regions, as well as mutations affecting other residues in the SF3B1–SUGP1 interface, not only weaken or disrupt the interaction but also alter splicing similarly to SF3B1 cancer mutations. Finally, structural modeling of a trimeric protein complex reveals that the SF3B1–SUGP1 interaction “loops out” the G-patch for interaction with the helicase DHX15. Our study thus provides an unprecedented molecular view of a protein complex essential for accurate splicing and also reveals that numerous cancer-associated mutations disrupt the critical SF3B1–SUGP1 interaction.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.351154.123.
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Freely available online through the Genes & Development Open Access option.
- Received September 5, 2023.
- Accepted November 1, 2023.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
