Defining Environmental Influence on RNA Processing

Ribonucleases modulate the cellular response to our environment by driving RNA turnover across diverse RNA metabolic pathways; yet, our limited understanding of the molecular networks linking RNA processing to environmental stress hinders our knowledge of how these critical responses promote cell fitness and survival. The long-term goal of my research is to define how the environment exacerbates the

activity of human disease associated RNA processing factors. Mitochondria are central for stress adaptation and undergo dynamic alterations in RNA processing during environmental changes. As the powerhouse of the cell, the mitochondria supplies the necessary fuel for stress adaptation. PNPase plays a central role in mitochondrial homeostasis, but the underlying molecular mechanism regulating its

function remains a mystery. The PNPase exoribonuclease associates with the SUV3 helicase to form the mitochondrial RNA degradosome, which orchestrates mitochondrial RNA decay. PNPase is a metabolic sensor that fine-tunes RNA degradosome activity with the metabolic state of the cell through an unknown

mechanism. The central hypothesis of this proposal is that RNA processing plays vital roles in the cellular response to our environment. The rationale for this project is that uncovering the molecular basis for stress-responsive RNA processing complexes will provide a novel framework to understand how the

environment impacts critical RNA processing events. This proposal will study (1) How the mitochondrial RNA degradosome syncs RNA turnover with the metabolic state of the cell and (2) How the RNA degradosome recognize its RNA substrates for mitochondrial RNA surveillance. To achieve these goals, a multi-disciplinary program that includes hybrid structural biology, biochemistry, cell biology, and molecular

biology will be implemented to understand the regulation and function of the RNA degradosome in response to environmental stress and stimuli.