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Exercise and RNA Oxidation
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Emil List Larsen, Kristian Karstoft, Henrik Enghusen Poulsen
During the last decades, much interest has been on genetic predisposition; however, the post-gene regulatory mechanisms have also attracted attention. Especially, the biological functions of RNA have emerged during the discoveries of functional non-coding types of RNA, and new intricate regulatory roles are continually being discovered. Alongside, the consequences of chemical modifications of RNA are revealed and considered epitranscriptomic changes; important for protein synthesis, signaling, and cellular homeostasis (Li, Xiong and Yi, 2016; Jonkhout et al., 2017). Several different oxidative modifications of DNA have been discovered and given the close resemblance with the chemical structure of RNA, it is assumed that similar oxidation products of RNA exist (Poulsen et al., 2012). Nonetheless, only a few in vivo RNA oxidation products have been identified (Weimann et al., 2012, 2019). The primary focus has been on the oxidation product 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that corresponds to the DNA oxidation product; 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG). These oxidation products are chemically well described, and the low redox potential of guanosine compared with the other nucleotides makes guanosine more prone to oxidation. In addition, validated analysis methods for detection of 8-oxoGuo and 8-oxodG exist (Poulsen et al., 2014). Several oxidative species (e.g., hydroxyl radical or carbonate radical) may be responsible for the oxidative modifications of nucleic acids. It is likely to assume that the different cellular locations of RNA and DNA presume different sources of ROS. ROS generated in the cytosol (e.g., mitochondria ROS) may oxidize RNA to a greater extent than nuclear DNA. In addition to the cellular location, the chemical structure of RNA permit oxidation more than DNA. RNA is to a large extent found single-stranded and typically lacks protective proteins (Poulsen et al., 2014). DNA-repair mechanisms are essential and well-described. In contrast, RNA lacks a template strand for repair. Thus, if RNA repair mechanism exists, then the mechanism has to be different from DNA repair (i.e., without using a template strand) (Yan and Zaher, 2019), and it seems more likely that RNA is degraded instead of repaired (Poulsen et al., 2012). Due to the difference in structure and location between RNA and DNA, it is not a surprise that the amount of oxidized RNA is greater than oxidized DNA (Weimann, Belling and Poulsen, 2002).
Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
All cells of the body generally contain the same genome. However, it is the information stored within the epigenetic code that regulates many aspects of the genome and reveals itself across various physiological, pathological, and developmental stages including cellular/tissue differentiation and lineage commitment [364–366]. Epigenetics, a term coined by Waddington in 1942, is the study of heritable changes in gene expression that occur independently of the basic DNA sequence and results in a phenotype modification without genotype modification [366, 367]. Since genetic material is not physically changed, epigenetic programming guarantees the inheritance of untouched genomic information from parents to offspring [296, 364] The epigenetic code is cell- and tissue-specific, and the literature identifies over 90,000 individual and over 400 different types of epigenetic modifications [368]. Epigenetics plays a seminal role in cancer. The ‘two-hit' model proposed by Knudson suggests cancer initiation follows from the interconnection of independent epimutations (a heritable change in DNA that does not involve an actual DNA mutation) that silence tumor-suppressor genes (the first hit) and deleterious genetic mutations or deletions (the second hit) that disrupt normal cellular processes [369]. Furthermore, in cancer progression, signals from the tumor microenvironment influence cancer epigenomes because stress induced by the tumor environment (e.g., inflammation, hypoxia) and/or by the therapeutic intervention may reshape the chromatin landscape, engendering epigenetic plasticity. This can promote intrinsic cellular reprogramming and cancer stemness, the molecular processes governing the fundamental stem cell properties of self-renewal and propagation of differentiated daughter cells [370, 371]) by way of a slow-cycling or semiquiescent phenotype persister state (where cells are resistant to a wide range of treatments and remain viable under conditions that kill surrounding cells [371]), as well as epithelial-mesenchymal plasticity (i.e., the ability to reversibly switch between a static adherent state and detached mobile state [372]), messenger RNA epitranscriptomic regulation (different RNA modifications such as covalent modifications like methylation that are added to individual nucleotides to regulate the stability, translation, and immunogenicity of RNA molecules [373]), and resistance to therapy [268, 272, 283, 371, 374–376]. Therefore, it is both the nucleotide sequence and these additional epigenetic modifications that regulate the function of the mRNAs transcribed from a given gene [373].
RNA N6-methyladenosine methylation and skin diseases
Published in Autoimmunity, 2023
Yaqin Yu, Shuang Lu, Hui Jin, Huan Zhu, Xingyu Wei, Tian Zhou, Ming Zhao
In Summary, we systematically discussed the classification of m6A-regulating proteins and their biological function in physiological processes and skin pathology. m6A erasers, writers, and readers context-dependently and synergistically regulate the expression of critical transcription factors and cellular signalling pathways in dermatosis pathogenesis via an m6A-mediated RNA stabilising, shearing, transporting, and translation. Given the extensive implementation of epitranscriptomics studies, RNA m6A modification has been emerging as crucial post-transcriptional regulator of gene expression. Aberrant expression of m6A related proteins-writers, erasers, and readers-mediates the imbalance of multiple disease-associated targets and downstream signalling pathway by affecting mRNA stability and translation efficiency. The generalisability and content dependency of m6A determine that attentions should be paid to the clarification of quantitative m6A level at different sites and distinctive function of a given m6A modification in variable cells and disorders, including skin disease. The work of m6A in dermatology has been largely focussed on autoimmune disease and cancer. Whether m6A also participates in the pathogenesis of other skin diseases like infectious dermatosis, genodermatosis, and metabolic dermatosis, especially the respective underlying mechanisms, requires to be further elucidated. Besides the well-studied m6A modifiers addressed in this review, some newly identified regulators that have been barely discussed before, may have underestimated effects in cell homeostasis or pathological progress of dermatosis. m6A-based target identification and clinical interventions are now showing great potential in the management of dermatological diseases for both diagnostic and therapeutic purposes.
Quantifying RNA modifications by mass spectrometry: a novel source of biomarkers in oncology
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Amandine Amalric, Amandine Bastide, Aurore Attina, Armelle Choquet, Jerome Vialaret, Sylvain Lehmann, Alexandre David, Christophe Hirtz
In the coming years, cancer studies in the developing field of epitranscriptomics should translate into opportunities for clinical applications. Easy to perform, fast, cost-effective, sensitive and reproducible methods are needed to evaluate the diagnostic power of these potential biomarkers. MS approaches, especially LC-MS/MS, are particularly suited for quantifying modified nucleosides. The development and validation of reference analytical methods for RNA modifications as biomarkers will be essential to facilitate the successful implementation of RNA epigenetic assays for cancer diagnosis worldwide.
RNA A-to-I editing, environmental exposure, and human diseases
Published in Critical Reviews in Toxicology, 2021
It is commonly accepted that diseases occur as a result of interactions between molecular alterations and environmental factors (Soto and Sonnenschein 2010; Wu et al. 2016). Until now, various genetic and epigenetic factors in response to environmental exposures had been investigated in human cells to understand the disease etiology. However, there are still unclear points that need to be investigated by molecular alterations that have been poorly investigated. RNA modifications are the unique candidates of molecular alteration that could be integrated in various fields of biology and medicine. Overall, epitranscriptomics, a promising research field, is a critical field since the modifying of RNAs is involved in critical biological processes that are associated with diseases, mainly cancer. Currently, although the biological roles of most RNA modifications remain unclear, the biological function of several modifications, including m6A, m1A, A-to-I, m5C, and pseudouridine, have been well-documented and efforts seems to increase in the near future. Furthermore, some of them, such as m6A, have been identified as reversible and thus as a dynamic feature that may indicate the susceptibility to environmental exposures. Intriguingly, pseudouridine modification has been reported as irreversible unlike m6A; thus, irreversibility of pseudouridine is critical in response to stress or stimuli (Zhao and He 2015). Although the field is growing up, the main obstacle is lack of rapid, relatively simple, and cheap analysis methods to quantify RNA modifications in large population samples. Current methods require a large amount of RNAs and are also expensive to apply for large biological samples. However, despite several limitations, the epitranscriptomics field needs to be addressed in environmental exposure-health outcomes studies. At least, current methods could be applied for quantifying RNA modifications with small sample sizes obtained from in-vitro and animal studies.