Ghosh, Souvik and Ataman, Meric and Bak, Maciej and Börsch, Anastasiya and Schmidt, Alexander and Buczak, Katarzyna and Martin, Georges and Dimitriades, Beatrice and Herrmann, Christina J. and Kanitz, Alexander and Zavolan, Mihaela. (2022) CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis. Nucleic Acids Research, 50 (6). pp. 3096-3114.
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Abstract
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.
Faculties and Departments: | 05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Zavolan) 05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Proteomics (Schmidt) |
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UniBasel Contributors: | Zavolan, Mihaela and Ghosh, Souvik and Ataman, Meric and Bak, Maciej and Börsch, Anastasiya and Schmidt, Alexander and Buczak, Katarzyna and Martin, Georges and Dimitriades, Beatrice and Herrmann, Christina and Kanitz, Alexander |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Oxford University Press |
ISSN: | 0305-1048 |
e-ISSN: | 1362-4962 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 13 Apr 2022 10:23 |
Deposited On: | 13 Apr 2022 10:23 |
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