Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 32, Pages 9926-9931Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1500639112
Keywords
U2AF(65); pre-mRNA splicing; splicing inhibition; exon exclusion; SMN
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Funding
- National Research Foundation (NRF) of the Korean Ministry of Education, Science, and Technology
- integrative aging research center of Gwangju Institute of Science and Technology
- [NRF-2013-R1A1A2062582]
- [NRF-2013-R1A1A2061321]
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U2 snRNP auxiliary factor 65 kDa (U2AF(65)) is a general splicing factor that contacts polypyrimidine (Py) tract and promotes prespliceosome assembly. In this report, we show that U2AF(65) stimulates alternative exon skipping in spinal muscular atrophy (SMA)-related survival motor neuron (SMN) pre-mRNA. A stronger 5' splice-site mutation of alternative exon abolishes the stimulatory effects of U2AF(65). U2AF(65) overexpression promotes its own binding only on the weaker, not the stronger, Py tract. We further demonstrate that U2AF(65) inhibits splicing of flanking introns of alternative exon in both three-exon and two-exon contexts. Similar U2AF(65) effects were observed in Fas (Apo-1/CD95) pre-mRNA. Strikingly, we demonstrate that U2AF(65) even inhibits general splicing of adenovirus major late (Ad ML) or beta-globin pre-mRNA. Thus, we conclude that U2AF(65) possesses a splicing Inhibitory function that leads to alternative exon skipping.
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