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RNA modifications by oxidation: A novel disease mechanism?

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  1. RNA oxidation and iron levels in patients with diabetes

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  2. Changes in oxidative RNA and DNA modifications following one-week treatment with sevelamer: two randomized, placebo-controlled trials

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  3. Changes in urinary excretion of oxidative nucleic acid modifications in the week following Copenhagen Marathon 2018, Denmark

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  4. Elevated levels of 8-oxoGuo and 8-oxodG in individuals with severe mental illness - An autopsy-based study

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  1. Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study

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  2. Polygenic predisposition to breast cancer and the risk of coronary artery disease

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  3. Perinatal Whole Blood Zinc Status and Cytokines, Adipokines, and Other Immune Response Proteins

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  4. Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals

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  5. Clinical, Physiologic, and Behavioral Evaluation of Permanently Catheterized NMRI Mice

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The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed into RNA, and this RNA has been found to encompass various classes of novel regulatory RNAs, including, e.g., microRNAs. It is well known that DNA is constantly oxidized and repaired by complex genome maintenance mechanisms. Analogously, RNA also undergoes significant oxidation, and there are now convincing data suggesting that oxidation, and the consequent loss of integrity of RNA, is a mechanism for disease development. Oxidized RNA is found in a large variety of diseases, and interest has been especially devoted to degenerative brain diseases such as Alzheimer disease, in which up to 50-70% of specific mRNA molecules are reported oxidized, whereas other RNA molecules show virtually no oxidation. The iron-storage disease hemochromatosis exhibits the most prominent general increase in RNA oxidation ever observed. Oxidation of RNA primarily leads to strand breaks and to oxidative base modifications. Oxidized mRNA is recognized by the ribosomes, but the oxidation results in ribosomal stalling and dysfunction, followed by decreased levels of functional protein as well as the production of truncated proteins that do not undergo proper folding and may result in protein aggregation within the cell. Ribosomal dysfunction may also signal apoptosis by p53-independent pathways. There are very few reports on interventions that reduce RNA oxidation, one interesting observation being a reduction in RNA oxidation by ingestion of raw olive oil. High urinary excretion of 8-oxo-guanosine, a biomarker for RNA oxidation, is highly predictive of death in newly diagnosed type 2 diabetics; this demonstrates the clinical relevance of RNA oxidation. Taken collectively the available data suggest that RNA oxidation is a contributing factor in several diseases such as diabetes, hemochromatosis, heart failure, and β-cell destruction. The mechanism involves free iron and hydrogen peroxide from mitochondrial dysfunction that together lead to RNA oxidation that in turn gives rise to truncated proteins that may cause aggregation. Thus RNA oxidation may well be an important novel contributing mechanism for several diseases.
Original languageEnglish
JournalFree Radical Biology & Medicine
Volume52
Issue number8
Pages (from-to)1353-61
Number of pages9
ISSN0891-5849
DOIs
Publication statusPublished - 2012

ID: 34768985