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 the resulting widespread downregulation of metabolic transcripts are common events that arise in response to 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.