Splice site strength–dependent activity and genetic buffering by poly-G runs
Author(s)Xiao, Xinshu; Wang, Zefeng; Jang, Minyoung; Nutiu, Razvan; Wang, Eric T.; Burge, Christopher B.; ... Show more Show less
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Pre-mRNA splicing is regulated through the combinatorial activity of RNA motifs, including splice sites and splicing regulatory elements. Here we show that the activity of the G-run (polyguanine sequence) class of splicing enhancer elements is approx4-fold higher when adjacent to intermediate strength 5' splice sites (ss) than when adjacent to weak 5' ss, and approx1.3-fold higher relative to strong 5' ss. We observed this dependence on 5' ss strength in both splicing reporters and in global microarray and mRNA-Seq analyses of splicing changes following RNA interference against heterogeneous nuclear ribonucleoprotein (hnRNP) H, which cross-linked to G-runs adjacent to many regulated exons. An exon's responsiveness to changes in hnRNP H levels therefore depends in a complex way on G-run abundance and 5' ss strength. This pattern of activity enables G-runs and hnRNP H to buffer the effects of 5' ss mutations, augmenting both the frequency of 5' ss polymorphism and the evolution of new splicing patterns. Certain other splicing factors may function similarly.
DepartmentWhitaker College of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Biology
Nature Structural and Molecular Biology
Nature Publishing Group
Xiao, Xinshu et al. “Splice site strength–dependent activity and genetic buffering by poly-G runs.” Nature Structural & Molecular Biology 16 (2009): 1094-1100.
Author's final manuscript