Title |
Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival
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Published in |
PLoS Genetics, October 2016
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DOI | 10.1371/journal.pgen.1006384 |
Pubmed ID | |
Authors |
Dennis Liang Fei, Hayley Motowski, Rakesh Chatrikhi, Sameer Prasad, Jovian Yu, Shaojian Gao, Clara L. Kielkopf, Robert K. Bradley, Harold Varmus |
Abstract |
We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3' splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3' splice sites. Finally, we show that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo. In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele. Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele. |
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Geographical breakdown
Country | Count | As % |
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United States | 11 | 55% |
France | 1 | 5% |
Australia | 1 | 5% |
Unknown | 7 | 35% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 10 | 50% |
Scientists | 9 | 45% |
Practitioners (doctors, other healthcare professionals) | 1 | 5% |
Mendeley readers
Geographical breakdown
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United States | 1 | 1% |
Germany | 1 | 1% |
Unknown | 68 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 17 | 24% |
Researcher | 13 | 19% |
Student > Master | 8 | 11% |
Student > Bachelor | 6 | 9% |
Other | 3 | 4% |
Other | 9 | 13% |
Unknown | 14 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 28 | 40% |
Agricultural and Biological Sciences | 18 | 26% |
Medicine and Dentistry | 5 | 7% |
Nursing and Health Professions | 1 | 1% |
Physics and Astronomy | 1 | 1% |
Other | 1 | 1% |
Unknown | 16 | 23% |