2. Academic Validation
  3. CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis

CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis

  • Nucleic Acids Res. 2022 Apr 8;50(6):3096-3114. doi: 10.1093/nar/gkac114.
Souvik Ghosh 1,  Meric Ataman 1 2,  Maciej Bak 1 2,  Anastasiya Börsch 1 2,  Alexander Schmidt 3,  Katarzyna Buczak 3,  Georges Martin 1,  Beatrice Dimitriades 1,  Christina J Herrmann 1 2,  Alexander Kanitz 1 2,  Mihaela Zavolan 1 2
Affiliations

Affiliations

  • 1 Computational and Systems Biology, Biozentrum, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
  • 2 Swiss Institute of Bioinformatics, Biozentrum, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
  • 3 Proteomics Core Facility, Biozentrum, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
PMID: 35234914 DOI: 10.1093/nar/gkac114
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.

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