A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.

Disruptions in core cellular processes elicit stress responses that drive cell state changes leading to organismal phenotypes. Perturbations in the splicing machinery cause widespread mis-splicing, resulting in p53-dependent cell-state changes that give rise to cell-type specific phenotypes and disease. However, a unified framework for how cells respond to splicing perturbations, and how this response manifests itself in nuanced disease phenotypes, has yet to be established. Here, we show that a p53-stabilizing Mdm2 alternative splicing event and widespread downregulation of metabolic transcripts are common events that arise under various splicing perturbations in both cellular and organismal models. Together, our results classify a common cellular response to splicing perturbations, put forth a new mechanism behind the cell-type specific phenotypes that arise when splicing is broadly disrupted, and lend insight into the pleiotropic nature of the effects of p53 stabilization in disease. Overall design: To assay gene expression and splicing changes that occur when the splicing machinery is perturbed, we knocked-down Eftud2 with two independent shRNAs (shRNA1, shRNA2) in R1-mESCs and performed RNA-Seq. Non-targeting shRNA (nt-shRNA) used as control