U2AF1 mutations alter splice site recognition in hematological malignancies

Genome Research
Janine O IlaganRobert K Bradley


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 3' 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), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' 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 allele-specific 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 fun...Continue Reading


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Related Concepts

U2AF1 protein, human
DNMT3B protein, rat
H2AFY2 protein, human
FANCA protein, human
CASP8 protein, human
ATR protein, human
Splicing Factor U2AF
DNA (Cytosine-5-)-Methyltransferase
Genotoxic Stress
Histone H7

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