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PMID: 26216990 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Splicing inhibition of U2AF65 leads to alternative exon skipping.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 112 ·No. 32 ·2015-08-11 ·Pages 9926-31

Cho S, Moon H, Loh TJ, Jang HN, Liu Y, Zhou J, Ohn T, Zheng X, Shen H

Abstract

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 β-globin pre-mRNA. Thus, we conclude that U2AF(65) possesses a splicing Inhibitory function that leads to alternative exon skipping.

Keywords
SMN U2AF65 exon exclusion pre-mRNA splicing splicing inhibition
MeSH Terms
Alternative Splicing/genetics Base Sequence DNA-Binding Proteins/genetics Exons/genetics HEK293 Cells Humans Introns/genetics Molecular Sequence Data Nuclear Proteins/chemistry,genetics Protein Binding Protein Structure, Tertiary RNA Precursors/genetics,metabolism RNA Splice Sites/genetics Ribonucleoproteins/chemistry,genetics SMN Complex Proteins/genetics Splicing Factor U2AF Structure-Activity Relationship Transcription Factors/genetics Viral Proteins/genetics beta-Globins/genetics tau Proteins/genetics
Chemicals
DNA-Binding Proteins MLTF protein, adenovirus Nuclear Proteins RNA Precursors RNA Splice Sites Ribonucleoproteins SMN Complex Proteins Splicing Factor U2AF Transcription Factors U2AF2 protein, human Viral Proteins beta-Globins tau Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Cho Sunghee
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
Moon Heegyum
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
Loh Tiing Jen
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
Jang Ha Na
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
Liu Yongchao
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
Zhou Jianhua
JiangSu Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, China;
Ohn Takbum
Department of Cellular & Molecular Medicine, College of Medicine, Chosun University, Gwangju 501-759, Korea.
Zheng Xuexiu
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
Shen Haihong
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea; [email protected].
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1500639112
Email
[email protected]
Published
2015-08-11
Epub
2015-00-27
Pages
9926-31
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4538632
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.1500639112 PMC Full Text View journal details
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