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

Area of Science:

• Molecular Biology
• Cellular Stress Responses
• Genetics

Background:

• Cellular processes, including splicing, are critical for organismal health.
• Splicing machinery disruptions trigger stress responses and cell-state changes.
• p53-dependent pathways are implicated in cell-type-specific diseases arising from splicing errors.

Purpose of the Study:

• To establish a unified framework for cellular responses to splicing perturbations.
• To elucidate the mechanism linking splicing disruptions to cell-type-specific disease phenotypes.
• To understand the role of p53 stabilization in diverse disease contexts.

Main Methods:

• Investigated cellular and organismal models subjected to various splicing perturbations.
• Analyzed alternative splicing events, focusing on p53-stabilizing events like Mdm2.
• Quantified transcriptomic changes, particularly the downregulation of metabolic genes.

Main Results:

• Identified a common splicing perturbation response involving p53 stabilization via Mdm2 alternative splicing.
• Observed widespread downregulation of metabolic transcripts as a conserved consequence.
• Demonstrated these events occur across diverse cellular and organismal models.

Conclusions:

• Classified a common cellular response to splicing perturbations.
• Proposed a novel mechanism for cell-type-specific phenotypes in splicing-disrupted diseases.
• Provided insights into the multifaceted effects of p53 stabilization in disease pathogenesis.