Lapendry, A. | Search bioRxiv

bioRxiv2023

SplicingLore: a web resource for studying the regulation of cassette exons by human splicing factors

One challenge faced by scientists from the alternative RNA splicing field is to decode the cooperative or antagonistic effects of splicing factors to understand and eventually predict splicing outcomes on a genome-wide scale. In this manuscript, we introduce SplicingLore, an open access database and web resource that help to fill this gap in a straightforward manner. The database contains a collection of RNA-seq-derived lists of alternative exons regulated by a total of 75 different splicing factors. All datasets were processed in a standardized manner, ensuring valid comparisons and correlation analyses. The user can easily retrieve a factor-specific set of differentially included exons from the database, or provide a list of exons and search which splicing factor(s) control(s) their inclusion. Our simple workflow is fast and easy to run, and it ensures a reliable calculation of correlation scores between the tested datasets. As a proof of concept, we predicted and experimentally validated a novel functional cooperation between the RNA helicases DDX17 and DDX5 and the HNRNPC protein. SplicingLore is available at https://splicinglore.ens-lyon.fr/.

genomics↗

bioRxiv2023

Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair

Amino acid bioavailability impacts mRNA translation in a codon depending manner. Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This results in the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate- and glutamate-rich proteins mostly involved in DNA metabolism. Consequently, cells that survive to MAPKi degrade aspartate and glutamate to generate energy, which simultaneously decreases their needs in amino acids owing to the downregulation of aspartate- and glutamate-rich proteins involved in cell proliferation. Concomitantly, the downregulation of aspartate- and glutamate-rich proteins involved in DNA repair increases DNA damage loads. Thus, DNA repair defects, and therefore mutations, are, at least in part, a secondary effect of the metabolic adaptation of cells exposed to MAPKi.

cancer biology↗