Relocalization RNA pseudoU (Ψ) writer proteins induced byair pollution

Ambient air pollution is an environmental toxin encountered by 99% of world’s population that poses a risk to the development of a broad range of health effects, primarily associated with cardiovascular and pulmonary diseases. Despite the well-documented danger to human health, the molecular programs that contribute to these environmental stress-induced disease states remain to be discovered. The structure and function of RNA molecules is modulated through their post-transcriptional modifications, with >150 different modifications having been observed in RNAs. It is increasingly clear that changes in the landscape of RNA modifications (the collection of RNA modifications and their transcriptomic positions at a given time) occur in response to environmental changes. We propose that exposure to air pollution induces shifts the RNA modification landscape that modulates the cellular responses to airborne toxins. In line with this hypothesis, the most prevalent modification in protein coding messenger RNAs (mRNAs), N6-methyladenosine (m6A), is associated with air pollution, particularly particulate matter (PM2.5). However, few studies have investigated mRNA modifications beyond m6A in the context of relevant environmental exposures. Here, we will establish how the RNA modification pseudouridine (Ψ) contributes to cellular responses to air pollution. Ψ is nearly as abundant as m6A in eukaryotic mRNAs, and is primarily found in mRNA coding regions where it is reported to alter the speed and accuracy of protein synthesis. Our preliminary data reveal that Ψ-incorporating enzymes (pseudouridine synthases) can change their subcellular localization in response to toxins found in air pollution. This relocalization appears to correlate with a re-shaping of the mRNA-modification landscape and changes in cellular fitness under stress. The work proposed herein will: 1) Determine if subcellular changes in pseudouridine synthase localization is a conserved environmental stress response, 2) Establish the molecular factors that contribute to stress-dependent localization, and 3) Characterize the impact of pseudouridine synthase relocalization on Ψ landscape and cellular health. Our initial findings lead us to posit that relocalization of RNA-modifying enzymes might be an important general component of cellular stress responses by contributing to altered RNA modification patterns that benefit cellular health under environmental stress. The findings of this study have the potential to open new avenues of investigation by revealing a novel mechanism used by cells to reprogram protein expression in response to environmental stress. Furthermore, they will provide much needed molecular level mechanistic insight into how air pollution-induced disease states arise. . Project Number: 1R21ES038333-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Lydia Contreras (+1 co-PI) | Institution: UNIVERSITY OF TEXAS AT AUSTIN, AUSTIN, TX | Award Amount: $415,906 | Activity Code: R21 | Study Section: Environmental Determinants of Disease Study Section [EDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288571