First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal
Alternative splicing accounts for much of the complexity in higher eukaryotes. Thus, its regulation must allow for flexibility without hampering either its specificity or its fidelity. The mechanisms involved in alternative splicing regulation, especially those acting through coupling with transcrip...
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2010
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13558382_v16_n5_p904_DeLaMatta http://hdl.handle.net/20.500.12110/paper_13558382_v16_n5_p904_DeLaMatta |
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paper:paper_13558382_v16_n5_p904_DeLaMatta2023-06-08T16:11:13Z First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal Alternative splicing Coupling Order of intron removal Pol II elongation transcription elongation factor alternative RNA splicing article exon gene cassette human human cell intron mutation priority journal spliceosome Alternative Splicing Base Sequence Cell Line DNA Polymerase II DNA Primers Exons Fibronectins Humans Introns Kinetics Models, Biological Mutation RNA Precursors RNA Splice Sites Transfection Eukaryota Alternative splicing accounts for much of the complexity in higher eukaryotes. Thus, its regulation must allow for flexibility without hampering either its specificity or its fidelity. The mechanisms involved in alternative splicing regulation, especially those acting through coupling with transcription, have not been deeply studied in in vivo models. Much of our knowledge comes from in vitro approaches, where conditions can be precisely controlled at the expense of losing several levels of regulation present in intact cells. Here we studied the relative order of removal of the introns flanking a model alternative cassette exon. We show that there is a preferential removal of the intron downstream from the cassette exon before the upstream intron has been removed. Most importantly, both cis-acting mutations and trans-acting factors that regulate the model alternative splicing event differentially affect the relative order of removal. However, reduction of transcriptional elongation causing higher inclusion of the cassette exon does not change the order of intron removal, suggesting that the assumption, according to the "first come, first served" model, that slow elongation promotes preferential excision of the upstream intron has to be revised. We propose instead that slow elongation favors commitment to exon inclusion during spliceosome assembly. Our results reveal that measuring the order of intron removal may be a straightforward read-out to discriminate among different mechanisms of alternative splice site selection. 2010 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13558382_v16_n5_p904_DeLaMatta http://hdl.handle.net/20.500.12110/paper_13558382_v16_n5_p904_DeLaMatta |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Alternative splicing Coupling Order of intron removal Pol II elongation transcription elongation factor alternative RNA splicing article exon gene cassette human human cell intron mutation priority journal spliceosome Alternative Splicing Base Sequence Cell Line DNA Polymerase II DNA Primers Exons Fibronectins Humans Introns Kinetics Models, Biological Mutation RNA Precursors RNA Splice Sites Transfection Eukaryota |
| spellingShingle |
Alternative splicing Coupling Order of intron removal Pol II elongation transcription elongation factor alternative RNA splicing article exon gene cassette human human cell intron mutation priority journal spliceosome Alternative Splicing Base Sequence Cell Line DNA Polymerase II DNA Primers Exons Fibronectins Humans Introns Kinetics Models, Biological Mutation RNA Precursors RNA Splice Sites Transfection Eukaryota First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| topic_facet |
Alternative splicing Coupling Order of intron removal Pol II elongation transcription elongation factor alternative RNA splicing article exon gene cassette human human cell intron mutation priority journal spliceosome Alternative Splicing Base Sequence Cell Line DNA Polymerase II DNA Primers Exons Fibronectins Humans Introns Kinetics Models, Biological Mutation RNA Precursors RNA Splice Sites Transfection Eukaryota |
| description |
Alternative splicing accounts for much of the complexity in higher eukaryotes. Thus, its regulation must allow for flexibility without hampering either its specificity or its fidelity. The mechanisms involved in alternative splicing regulation, especially those acting through coupling with transcription, have not been deeply studied in in vivo models. Much of our knowledge comes from in vitro approaches, where conditions can be precisely controlled at the expense of losing several levels of regulation present in intact cells. Here we studied the relative order of removal of the introns flanking a model alternative cassette exon. We show that there is a preferential removal of the intron downstream from the cassette exon before the upstream intron has been removed. Most importantly, both cis-acting mutations and trans-acting factors that regulate the model alternative splicing event differentially affect the relative order of removal. However, reduction of transcriptional elongation causing higher inclusion of the cassette exon does not change the order of intron removal, suggesting that the assumption, according to the "first come, first served" model, that slow elongation promotes preferential excision of the upstream intron has to be revised. We propose instead that slow elongation favors commitment to exon inclusion during spliceosome assembly. Our results reveal that measuring the order of intron removal may be a straightforward read-out to discriminate among different mechanisms of alternative splice site selection. |
| title |
First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| title_short |
First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| title_full |
First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| title_fullStr |
First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| title_full_unstemmed |
First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| title_sort |
first come, first served revisited: factors affecting the same alternative splicing event have different effects on the relative rates of intron removal |
| publishDate |
2010 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13558382_v16_n5_p904_DeLaMatta http://hdl.handle.net/20.500.12110/paper_13558382_v16_n5_p904_DeLaMatta |
| _version_ |
1768546315784945664 |