A Common Cellular Response to Broad Splicing Perturbations

Abstract

Cells are constantly experiencing stress that arises from external environmental factors or internal dysfunction. Despite this, cells are remarkably robust, and possess organized cellular response pathways to adapt to stress. Cellular stress responses to disruptions in many steps of the central dogma - from DNA synthesis to post-translational protein processing - are well classified. However, we have yet to establish a unifying mechanism describing how cells respond to disruptions in the process of mRNA splicing. Here, I demonstrate that a p53-stabilizing Mdm2 alternative splicing event is a common feature that arises under broad splicing perturbations. I then demonstrate that the resulting p53 stabilization propagates downregulation of metabolic transcripts. Furthermore, I show that this metabolic alteration is relevant to tissue-specific disorders that arise due to mutations in splicing factors, and other disorders of aberrant p53 stabilization, more broadly. Together, this work elucidates common components of a cellular response to broad splicing perturbations that are similar to other cellular stress responses, and lends insight into molecular mechanisms of splicing-associated developmental disorders.