Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast
Most eukaryotic mRNAs accommodate alternative sites of poly(A) addition in the 3’ untranslated region in order to regulate mRNA function. Here, we present a systematic analysis of 3’ end formation factors, which revealed 3’UTR lengthening in response to a loss of the core machinery, whereas a loss o...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/65331 |
| _version_ | 1828221486635155456 |
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| author | Rachael Emily Turner Paul F Harrison Angavai Swaminathan Calvin A Kraupner-Taylor Belinda J Goldie Michael See Amanda L Peterson Ralf B Schittenhelm David R Powell Darren J Creek Bernhard Dichtl Traude H Beilharz |
| author_facet | Rachael Emily Turner Paul F Harrison Angavai Swaminathan Calvin A Kraupner-Taylor Belinda J Goldie Michael See Amanda L Peterson Ralf B Schittenhelm David R Powell Darren J Creek Bernhard Dichtl Traude H Beilharz |
| author_sort | Rachael Emily Turner |
| collection | DOAJ |
| description | Most eukaryotic mRNAs accommodate alternative sites of poly(A) addition in the 3’ untranslated region in order to regulate mRNA function. Here, we present a systematic analysis of 3’ end formation factors, which revealed 3’UTR lengthening in response to a loss of the core machinery, whereas a loss of the Sen1 helicase resulted in shorter 3’UTRs. We show that the anti-cancer drug cordycepin, 3’ deoxyadenosine, caused nucleotide accumulation and the usage of distal poly(A) sites. Mycophenolic acid, a drug which reduces GTP levels and impairs RNA polymerase II (RNAP II) transcription elongation, promoted the usage of proximal sites and reversed the effects of cordycepin on alternative polyadenylation. Moreover, cordycepin-mediated usage of distal sites was associated with a permissive chromatin template and was suppressed in the presence of an rpb1 mutation, which slows RNAP II elongation rate. We propose that alternative polyadenylation is governed by temporal coordination of RNAP II transcription and 3’ end processing and controlled by the availability of 3’ end factors, nucleotide levels and chromatin landscape. |
| first_indexed | 2024-04-12T16:41:50Z |
| format | Article |
| id | doaj.art-ecd3bb4698f6403cb5fb9e82edf942a6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:41:50Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ecd3bb4698f6403cb5fb9e82edf942a62022-12-22T03:24:45ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.65331Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeastRachael Emily Turner0https://orcid.org/0000-0001-9319-4825Paul F Harrison1https://orcid.org/0000-0002-3980-268XAngavai Swaminathan2Calvin A Kraupner-Taylor3Belinda J Goldie4Michael See5https://orcid.org/0000-0002-7231-3896Amanda L Peterson6Ralf B Schittenhelm7David R Powell8Darren J Creek9Bernhard Dichtl10Traude H Beilharz11https://orcid.org/0000-0002-8942-9502Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, AustraliaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia; Monash Bioinformatics Platform, Monash University, Melbourne, AustraliaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, AustraliaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, AustraliaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, AustraliaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia; Monash Bioinformatics Platform, Monash University, Melbourne, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, AustraliaMonash Proteomics & Metabolomics Facility, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, AustraliaMonash Bioinformatics Platform, Monash University, Melbourne, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, AustraliaSchool of Life and Environmental Sciences, Deakin University, Geelong, AustraliaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, AustraliaMost eukaryotic mRNAs accommodate alternative sites of poly(A) addition in the 3’ untranslated region in order to regulate mRNA function. Here, we present a systematic analysis of 3’ end formation factors, which revealed 3’UTR lengthening in response to a loss of the core machinery, whereas a loss of the Sen1 helicase resulted in shorter 3’UTRs. We show that the anti-cancer drug cordycepin, 3’ deoxyadenosine, caused nucleotide accumulation and the usage of distal poly(A) sites. Mycophenolic acid, a drug which reduces GTP levels and impairs RNA polymerase II (RNAP II) transcription elongation, promoted the usage of proximal sites and reversed the effects of cordycepin on alternative polyadenylation. Moreover, cordycepin-mediated usage of distal sites was associated with a permissive chromatin template and was suppressed in the presence of an rpb1 mutation, which slows RNAP II elongation rate. We propose that alternative polyadenylation is governed by temporal coordination of RNAP II transcription and 3’ end processing and controlled by the availability of 3’ end factors, nucleotide levels and chromatin landscape.https://elifesciences.org/articles/65331alternative polyadenylationtranscription elongationcleavagepolyadenylationcordycepinmycophenolic acid |
| spellingShingle | Rachael Emily Turner Paul F Harrison Angavai Swaminathan Calvin A Kraupner-Taylor Belinda J Goldie Michael See Amanda L Peterson Ralf B Schittenhelm David R Powell Darren J Creek Bernhard Dichtl Traude H Beilharz Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast eLife alternative polyadenylation transcription elongation cleavage polyadenylation cordycepin mycophenolic acid |
| title | Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast |
| title_full | Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast |
| title_fullStr | Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast |
| title_full_unstemmed | Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast |
| title_short | Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast |
| title_sort | genetic and pharmacological evidence for kinetic competition between alternative poly a sites in yeast |
| topic | alternative polyadenylation transcription elongation cleavage polyadenylation cordycepin mycophenolic acid |
| url | https://elifesciences.org/articles/65331 |
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