FOX-2 dependent splicing of ataxin-2 transcript is affected by ataxin-1 overexpression.

Abstract

Alternative splicing is a fundamental posttranscriptional mechanism for controlling gene expression, and splicing defects have been linked to various human disorders. The splicing factor FOX-2 is part of a main protein interaction hub in a network related to human inherited ataxias, however, its impact remains to be elucidated. Here, we focused on the reported interaction between FOX-2 and ataxin-1, the disease-causing protein in spinocerebellar ataxia type 1. In this line, we further evaluated this interaction by yeast-2-hybrid analyses and co-immunoprecipitation experiments in mammalian cells. Interestingly, we discovered that FOX-2 localization and splicing activity is affected in the presence of nuclear ataxin-1 inclusions. Moreover, we observed that FOX-2 directly interacts with ataxin-2, a protein modulating spinocerebellar ataxia type 1 pathogenesis. Finally, we provide evidence that splicing of pre-mRNA of ataxin-2 depends on FOX-2 activity, since reduction of FOX-2 levels led to increased skipping of exon 18 in ataxin-2 transcripts. Most striking, we observed that ataxin-1 overexpression has an effect on this splicing event as well. Thus, our results demonstrate that FOX-2 is involved in splicing of ataxin-2 transcripts and that this splicing event is altered by overexpression of ataxin-1.

• Authors: Franziska Welzel, Christian Kaehler, Melanie Isau, Linda Hallen, Hans Lehrach, Sylvia Krobitsch
• Journal: PloS one (PLoS One) Vol. 7 Issue 5 Pg. e37985 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22666429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATXN1 protein, human
• Ataxin-1
• Ataxins
• Nerve Tissue Proteins
• Nuclear Proteins
• Protein Isoforms
• RBFOX2 protein, human
• RNA Splicing Factors
• RNA, Messenger
• RNA-Binding Proteins
• Repressor Proteins

Topics

• Alternative Splicing
• Ataxin-1
• Ataxins
• Cell Nucleus (metabolism)
• Gene Expression Regulation (genetics)
• HEK293 Cells
• HeLa Cells
• Humans
• Nerve Tissue Proteins (genetics)
• Nuclear Proteins (genetics)
• Protein Binding
• Protein Isoforms (metabolism)
• Protein Transport
• RNA Splicing Factors
• RNA, Messenger (genetics, metabolism)
• RNA-Binding Proteins (metabolism)
• Repressor Proteins (metabolism)