Oxidative Stress and RNA Damage Mechanisms

Oxidative stress arises when the generation of reactive oxygen species overwhelms cellular antioxidant defences, leading to chemical damage of biomolecules. While DNA lesions have been extensively characterised, RNA is now recognised as equally or more susceptible to oxidative insults owing to its single-stranded nature and proximity to sites of reactive oxygen species production. Common oxidative modifications include the formation of 8-oxo-7,8-dihydroguanine and strand breaks, as well as covalent adducts formed by environmental chemicals. Such damage can impair mRNA translation fidelity, disrupt ribosomal function and alter post-transcriptional regulation, with consequences for protein homeostasis and cell viability. Cells counteract RNA damage through quality-control pathways involving specialised ribonucleases, RNA-binding proteins and enzymatic removal or repair of lesions. These mechanisms operate across diverse organisms, from bacteria to human tissues, and their dysregulation is implicated in ageing, neurodegeneration, inflammation and cancer. Recent advances have begun to map the global landscape of RNA oxidation, reveal its role in early stress responses and identify molecular sensors that transduce oxidative signals into adaptive or maladaptive outcomes. Understanding the interplay between oxidative stress and RNA damage is crucial for developing biomarkers of exposure and interventions that preserve RNA integrity in health and disease.

Research from Nature Portfolio

Studies of human bronchial epithelial cells exposed to low-level formaldehyde have revealed selective oxidation of specific transcripts involved in chromatin modification and p53-mediated DNA-damage responses. Profiling of oxidised RNA by immunocapture and sequencing showed that early oxidative events in RNA coincide with minimal cytotoxicity, suggesting a role for transcript-specific oxidation in the initiation of carcinogenic pathways.

Investigation of air pollution mixtures on lung epithelial cells has uncovered targeted 8-oxoG formation in transcripts of the cholesterol biosynthesis enzyme FDFT1. Oxidation led to decreased mRNA and protein levels, reduced cholesterol synthesis and altered cell morphology. Knockdown of FDFT1 reproduced key pulmonary stress phenotypes, pointing to selective RNA oxidation as a mechanistic link between environmental exposure and bronchial dysfunction.

Oxidative Stress and RNA Damage Mechanisms publication trend

The graph below shows the total number of articles in oxidative stress and rna damage mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Partially reduced oxygen derivatives that can oxidise nucleic acids, proteins and lipids.

8-oxo-7,8-dihydroguanine (8-oxoG): A common oxidative lesion of the guanine base that can miscode during translation.

RNA adduct: A covalent modification of a nucleobase or sugar–phosphate backbone by endogenous or exogenous electrophiles.

Ribonucleoprotein complex (RNP): An assembly of RNA molecules with associated proteins that carry out or regulate RNA functions.

RNA quality control: Cellular surveillance pathways that detect and remove damaged or aberrant RNA species to maintain transcriptome integrity.

References

1. RNAs as Sensors of Oxidative Stress in Bacteria. Annual Review of Chemical and Biomolecular Engineering (2023).
2. Discovery of an 8-oxoguanine regulator PCBP1 inhibitor by virtual screening and its synergistic effects with ROS-modulating agents in pancreatic cancer. Frontiers in Molecular Biosciences (2024).
3. Characterizing Benzo[a]pyrene Adducts in Transfer RNAs Using Liquid Chromatography Coupled with Tandem Mass Spectrometry (LC-MS/MS). Biomedicines (2023).
4. RNA oxidation in chromatin modification and DNA-damage response following exposure to formaldehyde. Scientific Reports (2020).
5. Post-transcriptional air pollution oxidation to the cholesterol biosynthesis pathway promotes pulmonary stress phenotypes. Communications Biology (2020).