Abstract
The spliceosomal geneSF3B1is frequently mutated in cancer. While it is known thatSF3B1hotspot 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 toSF3B1cancer 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.
Funder
National Natural Science Foundation of China
Beijing Natural Science Foundation
Chinese Academy of Sciences Hundred Talents Program
National Institutes of Health
European Research Council
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
2 articles.
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