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CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis

The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-om...

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Autores principales: Ghosh, Souvik, Ataman, Meric, Bak, Maciej, Börsch, Anastasiya, Schmidt, Alexander, Buczak, Katarzyna, Martin, Georges, Dimitriades, Beatrice, Herrmann, Christina J, Kanitz, Alexander, Zavolan, Mihaela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989530/
https://www.ncbi.nlm.nih.gov/pubmed/35234914
http://dx.doi.org/10.1093/nar/gkac114
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author Ghosh, Souvik
Ataman, Meric
Bak, Maciej
Börsch, Anastasiya
Schmidt, Alexander
Buczak, Katarzyna
Martin, Georges
Dimitriades, Beatrice
Herrmann, Christina J
Kanitz, Alexander
Zavolan, Mihaela
author_facet Ghosh, Souvik
Ataman, Meric
Bak, Maciej
Börsch, Anastasiya
Schmidt, Alexander
Buczak, Katarzyna
Martin, Georges
Dimitriades, Beatrice
Herrmann, Christina J
Kanitz, Alexander
Zavolan, Mihaela
author_sort Ghosh, Souvik
collection PubMed
description The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that >800 genes undergo coherent APA in response to changes in CFIm levels, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the fluctuations in cell growth and metabolism that are observed upon CFIm perturbations. Furthermore, multiple transcripts encoding proteins from the miRNA pathway are targets of CFIm-dependent APA. This leads to an increased biogenesis and repressive activity of miRNAs at the same time as some 3′ UTRs become shorter and presumably less sensitive to miRNA-mediated repression. Our study provides a first systematic assessment of a core set of APA targets that respond coherently to changes in CFIm protein subunit levels (CFIm25/CFIm68). We describe the elicited signaling pathways downstream of CFIm, which improve our understanding of the key role of CFIm in integrating RNA processing with other cellular activities.
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spelling pubmed-89895302022-04-08 CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis Ghosh, Souvik Ataman, Meric Bak, Maciej Börsch, Anastasiya Schmidt, Alexander Buczak, Katarzyna Martin, Georges Dimitriades, Beatrice Herrmann, Christina J Kanitz, Alexander Zavolan, Mihaela Nucleic Acids Res Computational Biology The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that >800 genes undergo coherent APA in response to changes in CFIm levels, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the fluctuations in cell growth and metabolism that are observed upon CFIm perturbations. Furthermore, multiple transcripts encoding proteins from the miRNA pathway are targets of CFIm-dependent APA. This leads to an increased biogenesis and repressive activity of miRNAs at the same time as some 3′ UTRs become shorter and presumably less sensitive to miRNA-mediated repression. Our study provides a first systematic assessment of a core set of APA targets that respond coherently to changes in CFIm protein subunit levels (CFIm25/CFIm68). We describe the elicited signaling pathways downstream of CFIm, which improve our understanding of the key role of CFIm in integrating RNA processing with other cellular activities. Oxford University Press 2022-03-02 /pmc/articles/PMC8989530/ /pubmed/35234914 http://dx.doi.org/10.1093/nar/gkac114 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Computational Biology
Ghosh, Souvik
Ataman, Meric
Bak, Maciej
Börsch, Anastasiya
Schmidt, Alexander
Buczak, Katarzyna
Martin, Georges
Dimitriades, Beatrice
Herrmann, Christina J
Kanitz, Alexander
Zavolan, Mihaela
CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
title CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
title_full CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
title_fullStr CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
title_full_unstemmed CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
title_short CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
title_sort cfim-mediated alternative polyadenylation remodels cellular signaling and mirna biogenesis
topic Computational Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989530/
https://www.ncbi.nlm.nih.gov/pubmed/35234914
http://dx.doi.org/10.1093/nar/gkac114
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