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Polyamine-dependent metabolic shielding regulates alternative splicing

GSE255769 Homo sapiens; Mus musculus Expression profiling by high throughput sequencing 144 samples Submitted 2025/11/11 Platform GPL16791Platform GPL24247Platform GPL24676
Summary
Metabolites are central to cellular homeostasis. Whereas much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signaling molecules. Here we show that polyamines, small polycations critical to cellular homeostasis1-3, regulate the process of alternative pre-mRNA splicing. We find that the inhibition of polyamine synthesis increases the phosphorylation of spliceosomal proteins, concomitant with a remarkable perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modeling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 snRNP SF3 subcomplex, thus preventing the action of kinases. The molecular process through which polyamines regulate protein phosphorylation is a phenomenon that we define as “metabolic shielding”.
Published in
Polyamine-dependent metabolic shielding regulates alternative splicing
Zabala-Letona A, Pujana-Vaquerizo M, Martinez-Laosa B et al. · Nature 2026 · PMID 41535471 · doi:10.1038/s41586-025-09965-1
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Direct links to NCBI, no account and no request form: the whole study as GSE255769_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 144 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1076496 and SRA study SRP489717. Searching any of these in the dataset finder brings you back here.

Study design
8 conditions, mostly with about 4 replicates each
Gastrocnemius, Veh, ×5 DU145 shAMD1 cells, DOX 48 hours, plate ×4 DU145 shAMD1 cells, noDOX, plate ×4 DU145 shAMD siSCR cells, noDOX, plate ×4 DU145 shAMD siSCR cells, DOX, plate ×4 DU145 shAMD siF3A3 cells, noDOX, plate ×4 DU145 shAMD siF3A3 cells, DOX, plate ×4 Gastrocnemius, SAM486A, ×3 +8 more

Supports a between-group comparison across 32 samples.

8 replicated groups read from the first 40 of 144 sample titles; they account for 32 of them. Check it against the sample list below before relying on it.

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