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Media type:
E-Article
Title:
Splice-Site Pairing Is an Intrinsically High Fidelity Process
Contributor:
Fox-Walsh, Kristi L.;
Hertel, Klemens J.;
Maniatis, Thomas
Published:
National Academy of Sciences, 2009
Published in:
Proceedings of the National Academy of Sciences of the United States of America, 106 (2009) 6, Seite 1766-1771
Language:
English
ISSN:
0027-8424
Origination:
Footnote:
Description:
<p>The extensive alternative splicing in higher eukaryotes has initiated a debate whether alternative mRNA isoforms are generated by an inaccurate spliceosome or are the consequence of highly degenerate splice sites within the human genome. Here, we established a quantitative assay to evaluate the accuracy of splicesite pairing by determining the number of incorrect exon-skipping events made from constitutively spliced pre-mRNA transcripts. We demonstrate that the spliceosome pairs exons with an astonishingly high degree of accuracy that may be limited by the quality of pre-mRNAs generated by RNA pol II. The error rate of exon pairing is increased by the effects of the neurodegenerative disorder spinal muscular atrophy because of reduced levels of Survival of Motor Neuron, a master assembler of spliceosomal components. We conclude that all multi-intron-containing genes are alternatively spliced and that the reduction of SMN results in a general splicing defect that is mediated through alterations in the fidelity of splice-site pairing.</p>