Role of Oxidative RNA Damage in Chronic-Degenerative Diseases

Fimognari, Carmela

doi:10.1155/2015/358713

Cited by 52 publications

(41 citation statements)

References 74 publications

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“…Our results are consistent with previous findings that RNA is vulnerable to oxidative damage [39–41]. Oxidative modification of RNA results in disturbance of the translational process and impairment of protein synthesis, which can cause cell deterioration or even cell death [43, 44]. Maintaining the integrity of rDNA is crucial for rRNA synthesis which is the initial step of ribosome biogenesis.…”

Section: Discussionsupporting

confidence: 92%

Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells

et al. 2016

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Acrolein (Acr) is a potent cytotoxic and DNA damaging agent which is ubiquitous in the environment and abundant in tobacco smoke. Acr is also an active cytotoxic metabolite of the anti-cancer drugs cyclophosphamide and ifosfamide. The mechanisms via which Acr exerts its anti-cancer activity and cytotoxicity are not clear. In this study, we found that Acr induces cytotoxicity and cell death in human cancer cells with different activities of p53. Acr preferentially binds nucleolar ribosomal DNA (rDNA) to form Acr-deoxyguanosine adducts, and induces oxidative damage to both rDNA and ribosomal RNA (rRNA). Acr triggers ribosomal stress responses, inhibits rRNA synthesis, reduces RNA polymerase I binding to the promoter of rRNA gene, disrupts nucleolar integrity, and impairs ribosome biogenesis and polysome formation. Acr causes an increase in MDM2 levels and phosphorylation of MDM2 in A549 and HeLa cells which are p53 active and p53 inactive, respectively. It enhances the binding of ribosomal protein RPL11 to MDM2 and reduces the binding of p53 and E2F-1 to MDM2 resulting in stabilization/activation of p53 in A549 cells and degradation of E2F-1 in A549 and HeLa cells. We propose that Acr induces ribosomal stress which leads to activation of MDM2 and RPL11-MDM2 binding, consequently, activates p53 and enhances E2F-1 degradation, and that taken together these two processes induce apoptosis and cell death.

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Section: Discussionsupporting

confidence: 92%

Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells

et al. 2016

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“…Furthermore, RNA bases are not protected by hydrogen bonding and specific proteins. These problems underlie the reasons that make RNA more vulnerable to oxidative damage than DNA (Fimognari ). While elevated oxidative stress in the cerebral cortex in patients with early‐stage PD has been described (Ferrer ); RNA oxidation has been prominently observed in post‐mortem AD brains with lesser volumes of Aβ plaque deposition or shorter disease duration (Nunomura et al ).…”

Section: Discussionmentioning

confidence: 99%

The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases

Yang

Knight

et al. 2019

Journal of Neurochemistry

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The striatum with a number of dopamine containing neurons, receiving projections from the substantia nigra and ventral tegmental area; plays a critical role in neurodegenerative diseases of motor and memory function. Additionally, oxidative damage to nucleic acid may be vital in the development of age-associated neurodegeneration. The metabolism of dopamine is recognized as one of the sources of reactive oxygen species through the Fenton mechanism. The proposed interactions of oxidative insults and dopamine in the striatum during the progression of diseases are the hypotheses of most interest to our study. This study investigated the possibility of significant interactions between these molecules that are involved in the late-stage of Alzheimer's disease (AD), Parkinson disease (PD), Parkinson disease dementia, dementia with Lewy bodies, and controls using ELISA assays, autoradiography, and mRNA in situ hybridization assay. Interestingly, lower DNA/RNA oxidative adducts levels in the caudate and putamen of diseased brains were observed with the exception of an increased DNA oxidative product in the caudate of AD brains. Similar changes were found for dopamine concentration and vesicular monoamine transporter 2 densities. We also found that downstream pre-synaptic dopamine D1 Receptor binding correlated with dopamine loss in Lewy body disease groups, and RNA damage and b-site APP cleaving enzyme 1 in the caudate of AD. This is the first demonstration of region-specific alterations of DNA/RNA oxidative damage which cannot be viewed in isolation, but rather in connection with the interrelationship between different neuronal events; chiefly DNA oxidative adducts and density of vesicular monoamine transporter 2 densities in AD and PD patients.

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“…A number of synthetic pH sensors are also available (Yang et al, 2014). Both genetically encoded and synthetic sensors of ROS are also available (Pouvreau, 2014; Swanson et al, 2011), which could be applied to study how ROS are associated with genetic diseases (Fimognari, 2015) or environmental conditions (Jaspers & Kangasjärvi, 2010) that affect RNA structure in vivo .…”

Section: Setting the Stagementioning

confidence: 99%

Bridging the gap betweenin vitroandin vivoRNA folding

Leamy

Assmann

Mathews

et al. 2016

Quart. Rev. Biophys.

123

132

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Deciphering the folding pathways and predicting the structures of complex three-dimensional biomolecules is central to elucidating biological function. RNA is single-stranded, which gives it the freedom to fold into complex secondary and tertiary structures. These structures endow RNA with the ability to perform complex chemistries and functions ranging from enzymatic activity to gene regulation. Given that RNA is involved in many essential cellular processes, it is critical to understand how it folds and functions in vivo. Within the last few years, methods have been developed to probe RNA structures in vivo and genome-wide. These studies reveal that RNA often adopts very different structures in vivo and in vitro, and provide profound insights into RNA biology. Nonetheless, both in vitro and in vivo approaches have limitations: studies in the complex and uncontrolled cellular environment make it difficult to obtain insight into RNA folding pathways and thermodynamics, and studies in vitro often lack direct cellular relevance, leaving a gap in our knowledge of RNA folding in vivo. This gap is being bridged by biophysical and mechanistic studies of RNA structure and function under conditions that mimic the cellular environment. To date, most artificial cytoplasms have used various polymers as molecular crowding agents and a series of small molecules as cosolutes. Studies under such in vivo-like conditions are yielding fresh insights, such as cooperative folding of functional RNAs and increased activity of ribozymes. These observations are accounted for in part by molecular crowding effects and interactions with other molecules. In this review, we report milestones in RNA folding in vitro and in vivo and discuss ongoing experimental and computational efforts to bridge the gap between these two conditions in order to understand how RNA folds in the cell.

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Role of Oxidative RNA Damage in Chronic-Degenerative Diseases

Cited by 52 publications

References 74 publications

Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells

Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells

The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases

Bridging the gap betweenin vitroandin vivoRNA folding

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