Journal
GENOME RESEARCH
Volume 25, Issue 1, Pages 14-26Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.181016.114
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Funding
- Hartwell Innovation Fund
- Damon Runyon Cancer Research Foundation [DFS 04-12]
- Ellison Medical Foundation [AG-NS-1030-13]
- NIH/NCI [P30 CA015704, T32 CA009657]
- Fred Hutchinson Cancer Research Center institutional funds
- NIH/NIDDK [P30 DK056465, K08 DK082783]
- NIH/NHLBI [U01 HL099993]
- J.P. McCarthy Foundation
- Storb Foundation
- NIH/NIGMS [R01 GM088277]
- NATIONAL CANCER INSTITUTE [T32CA009657, P30CA015704] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U01HL099993] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK082783, P30DK056465] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM088277] Funding Source: NIH RePORTER
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Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 39 splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), theDNAdamage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 39 splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allelespecific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1's zinc finger domains.
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