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TruD's Effect On RNA Oxidation
Title
TruD's Effect On RNA Oxidation.
Creator
Mills, Darius, Martin, Narelle, Rodriguez, Gabriela, Li, Zhongwei
Abstract/Description
Age-related neurodegenerative diseases impact society in an increasing rate. Oxidative damage to cellular molecules is considered the main cause of many neurological diseases such as, Alzheimer’s disease, Parkinson’s disease, etc. Understanding the mechanism and what cleans up oxidized molecules is vital in order to further explore therapeutic research for neurodegenerative diseases. RNA damage is potentially a major contributor to these diseases. However, compared to our knowledge about DNA,...
Show moreAge-related neurodegenerative diseases impact society in an increasing rate. Oxidative damage to cellular molecules is considered the main cause of many neurological diseases such as, Alzheimer’s disease, Parkinson’s disease, etc. Understanding the mechanism and what cleans up oxidized molecules is vital in order to further explore therapeutic research for neurodegenerative diseases. RNA damage is potentially a major contributor to these diseases. However, compared to our knowledge about DNA, little is known about the mechanism that cells use to eliminate damaged RNA. Our objective in this study is to understand the role of proteins that specifically bind oxidized RNA. We will focus on one such protein TruD in Escherichia coli. By studying how TruD and its mutants help E. coli to survive oxidative stress, we hope to elucidate a mechanism by which cells fight against RNA oxidation, and to suggest disease-preventing mechanisms by the human TruD homologs on a molecular level.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA0005030
Subject Headings
College students --Research --United States.
Format
Document (PDF)
Control of RNA oxidation as a novel mechanism for preventing mitochondrial dysfunction
Title
Control of RNA oxidation as a novel mechanism for preventing mitochondrial dysfunction.
Creator
Malla, Sulochan, Walker, Merritt, Graduate College, Li, Zhongwei
Abstract/Description
Mitochondria generate energy through oxidative phosphorylation in eukaryotic cell and produce large amount of reactive oxygen species ROS as byproducts during this process. In particular in mitochondria, oxidative modifications of biomolecules by ROS can cause their inactivation. The situation is exacerbated during oxidative stress when excessive amounts of ROS are produced. Oxidative damage of macromolecules causes mitochondrial dysfunction and eventually leads to numerous diseases such as...
Show moreMitochondria generate energy through oxidative phosphorylation in eukaryotic cell and produce large amount of reactive oxygen species ROS as byproducts during this process. In particular in mitochondria, oxidative modifications of biomolecules by ROS can cause their inactivation. The situation is exacerbated during oxidative stress when excessive amounts of ROS are produced. Oxidative damage of macromolecules causes mitochondrial dysfunction and eventually leads to numerous diseases such as cardiovascular and neural disorders. Although the deleterious effects of oxidized DNA, proteins and lipids have been extensively characterized, little is known about the potential causative effects of oxidized RNA. Here, we assessed RNA oxidation levels in the mitochondria and cytosol of cultured human cells, which was analyzed by using 8-hydroxyguanosine 8-oxo-G on the RNA as a marker for oxidative stress. Interestingly, our result revealed that 8-oxo-G levels of mitochondrial mt-RNA was relatively higher than that of cytosolic RNA suggesting that RNA is one of the contributing factors leading to mitochondrial dysfunction. To further evaluate the consequence of RNA oxidation, we will examine mitochondrial functionality, permeability, and cell viability to determine a correlation with the levels of 8-oxo-G in mt-RNA. We previously showed that human polynucleotide phosphorylase hPNPase, which mainly localizes to mitochondria and binds oxidized RNA with high affinity, reduces RNA oxidation and protects HeLa cell during oxidative stress. We intend to elucidate the potential role of hPNPase and its associated RNA helicase, hSUV3, in reducing mt-RNA oxidation which is of relevance to diseases associated with mitochondrial dysfunction.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00005156
Format
Document (PDF)
The Role of Exoribonucleases and MutT Pyrophosphohydrolase in the Surveillance of Oxidatively-damaged RNA
Title
The Role of Exoribonucleases and MutT Pyrophosphohydrolase in the Surveillance of Oxidatively-damaged RNA.
Creator
Zhang, Jianan, Li, Zhongwei, Florida Atlantic University
Abstract/Description
Three important exoribonucleases degrading RNAs in sequence-independent manner, RNase II, RNase Rand polynucleotide phosphorylase (PNPase), were shown to protect cells against oxidative stress. This is presumably due to the function of the exoribonucleases in the removal of oxidized RNA in cells. MutT pyrophosphohydrolase .was previously reported to scavenge oxidized nucleotides 8-oxoGTP and 8-oxoGDP, prevent their incorporation into RNA. Deficiency of MutT may lead to an increase in the...
Show moreThree important exoribonucleases degrading RNAs in sequence-independent manner, RNase II, RNase Rand polynucleotide phosphorylase (PNPase), were shown to protect cells against oxidative stress. This is presumably due to the function of the exoribonucleases in the removal of oxidized RNA in cells. MutT pyrophosphohydrolase .was previously reported to scavenge oxidized nucleotides 8-oxoGTP and 8-oxoGDP, prevent their incorporation into RNA. Deficiency of MutT may lead to an increase in the level of 8-oxoG in RNA, which may enhance the requirement of the RNA surveillance function of the exoribonucleases. This study focuses on the roles of the RNA-degradation exoribonucleases in the removal of oxidatively-damaged RNA in the mutT background. This work shows that mutT mutation enhances the sensitivity of the RNase mutants to hydrogen peroxide. Growth defect of the pnp mutT mutant was detected even under normal aeration, but was rescued to the level of pnp mutant under anaerobic conditions. The pnp mutT mutant shows high mutator activity observed from LacZ reporter system and high level of 8-oxoG in RNA, strongly suggest that PNPase is responsible for removing 8-oxoG containing RNAs elevated in mutT background. Additionally, genetic instability observed from the mutant lacking RNase II and MutT supports the idea that RNase II may adopt a distinct pathway to reduce deleterious effect from oxidation challenge.
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Date Issued
2007
PURL
http://purl.flvc.org/fau/fd/FA00000856
Subject Headings
Nucleic acids--Oxidation, DNA repair, Chemical mutagenesis
Format
Document (PDF)
tRNA processing and quality control in bacteria
Title
tRNA processing and quality control in bacteria.
Creator
Alluri, Ravi Kumar, Li, Zhongwei, Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description
In this work, we report that the only exoribonuclease in M. genitalium, RNase R, is able to generate mature 3'-ends. The aminoacyl-acceptor stem, CCA terminus and discriminator residue plays an important role in stopping RNase R digestion at the mature 3'-end. Disruption of the stem causes partial or complete degradation of the pre-tRNA, whereas extension of the stem results in the formation of a mature 3’-end. CC residues in CCA terminus and A or G residues at discriminator position are the...
Show moreIn this work, we report that the only exoribonuclease in M. genitalium, RNase R, is able to generate mature 3'-ends. The aminoacyl-acceptor stem, CCA terminus and discriminator residue plays an important role in stopping RNase R digestion at the mature 3'-end. Disruption of the stem causes partial or complete degradation of the pre-tRNA, whereas extension of the stem results in the formation of a mature 3’-end. CC residues in CCA terminus and A or G residues at discriminator position are the most preferred residues for precise stopping of RNase R at mature 3’ end. The significance of this works shows that M. genitalium RNase R generates mature tRNA in a single step by recognizing features in the terminal domains of tRNA, a process requiring multiple RNases in most bacteria.
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Date Issued
2013
PURL
http://purl.flvc.org/fau/fd/FA00004174
Format
Document (PDF)
Study on the Role oftmRNA in Protecting Escherichia coli Cell Under Oxidative stress.
Title
Study on the Role oftmRNA in Protecting Escherichia coli Cell Under Oxidative stress.
Creator
Kollipara, Gayatri, Li, Zhongwei, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
tmRNA is a small stable RNA present in Eubacteria. Through a mechanism called trans-translation, tmRNA mediates ribosome rescue and quality control of proteins and mRNA. In this study, the Escherichia coli (E. coli) mutant lacking tmRNA was demonstrated hypersensitive to oxidative stress. The role of tmRNA-mediated surveillance mechanism in protecting E. coli cell under oxidative stress condition was examined. The tmRNA-mediated tagged protein levels were elevated in cells under oxidative...
Show moretmRNA is a small stable RNA present in Eubacteria. Through a mechanism called trans-translation, tmRNA mediates ribosome rescue and quality control of proteins and mRNA. In this study, the Escherichia coli (E. coli) mutant lacking tmRNA was demonstrated hypersensitive to oxidative stress. The role of tmRNA-mediated surveillance mechanism in protecting E. coli cell under oxidative stress condition was examined. The tmRNA-mediated tagged protein levels were elevated in cells under oxidative stress condition, demonstrating the enhanced need for tmRNA under such condition. Our results suggest that mRNA damage by oxidative stress may cause reduced cell viability, and that tmRNA is required to rescue cells under such condition. Furthermore, our observations showed that tmRNA is required for the optimal growth of E. coli under normal aeration but not under anaerobic condition, suggesting that oxidation ofmRNA is the major reason for requirement oftmRNA during normal aeration.
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Date Issued
2007
PURL
http://purl.flvc.org/fau/fd/FA00000782
Subject Headings
Proteins--Synthesis, Bacterial genetics, Escherichia coli infections, Cells--Evolution
Format
Document (PDF)
A Study on the Potential Role of Stress Granules and Processing Bodies in Eliminating Oxidatively Damaged RNA
Title
A Study on the Potential Role of Stress Granules and Processing Bodies in Eliminating Oxidatively Damaged RNA.
Creator
Pourkalbassi, Delaram, Li, Zhongwei, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Oxidative stress (OS) is strongly implicated in age-related neurodegeneration and other diseases. Under OS, the production of excessive oxidants leads to increased damages to cellular components. Recently, RNA has been discovered as a major target of oxidative damage, including the creation of abasic sites. In this work, we developed a method for quantifying abasic RNA in cell. Using this method, we have examined the potential role of the RNA-processing cellular foci, stress granule (SG) and...
Show moreOxidative stress (OS) is strongly implicated in age-related neurodegeneration and other diseases. Under OS, the production of excessive oxidants leads to increased damages to cellular components. Recently, RNA has been discovered as a major target of oxidative damage, including the creation of abasic sites. In this work, we developed a method for quantifying abasic RNA in cell. Using this method, we have examined the potential role of the RNA-processing cellular foci, stress granule (SG) and processing bodies (PB) in eliminating abasic RNA in situ. We demonstrated that RNA is a major target of oxidative damage, constituting the majority of OS-induced abasic nucleic acids in HeLa cell. Importantly, the level of abasic RNA is strongly correlated with SG abundance. Furthermore, inhibition of SG/PB formation causes accumulation of abasic RNA, suggesting that SG/PB participates in removing oxidized RNA and protects cells under OS, which offers novel targets for therapeutic intervention in age-related diseases.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004702
Subject Headings
Aging -- Physiological aspects., Oxidative stress., RNA -- Metabolism.
Format
Document (PDF)
DISCOVERY OF GENES AND MOLECULAR PROCESSES THAT ARE IMPORTANT FOR THE PATHOGENESIS OF ALZHEIMER’S DISEASE
Title
DISCOVERY OF GENES AND MOLECULAR PROCESSES THAT ARE IMPORTANT FOR THE PATHOGENESIS OF ALZHEIMER’S DISEASE.
Creator
Kwakye, Alexander, Li, Zhongwei, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Medicine
Abstract/Description
Alzheimer’s Disease (AD) is a complex brain disorder that affects at least one in every ten persons aged 65 and above worldwide. The pathogenesis of this disorder remains elusive. In this work, we utilized a rich set of publicly available gene expression data to elucidate the genes and molecular processes that may underlie its pathogenesis. We developed a new ranking score to prioritize molecular pathways enriched in differentially expressed genes during AD. After applying our new ranking...
Show moreAlzheimer’s Disease (AD) is a complex brain disorder that affects at least one in every ten persons aged 65 and above worldwide. The pathogenesis of this disorder remains elusive. In this work, we utilized a rich set of publicly available gene expression data to elucidate the genes and molecular processes that may underlie its pathogenesis. We developed a new ranking score to prioritize molecular pathways enriched in differentially expressed genes during AD. After applying our new ranking score, GO categories such as cotranslational protein targeting to membrane, SRP-dependent cotranslational protein targeting to membrane, and spliceosomal snRNP assembly were found to be significantly associated with AD. We also confirm the protein-protein interaction between APP, NPAS4 and ARNT2 and explain that this interaction could be implicated in AD. This interaction could serve as a theoretical framework for further analyses into the role of NPAS4 and other immediate-early genes in AD pathogenesis.
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Date Issued
2020
PURL
http://purl.flvc.org/fau/fd/FA00013541
Subject Headings
Alzheimer's disease, Alzheimer's disease--Genetic aspects, Alzheimer's disease--Molecular aspects, Alzheimer's disease--Pathogenesis
Format
Document (PDF)
Unraveling the molecular mechanism of human polynucleotide phosphorylase (hPNPase) in controlling oxidized RNA
Title
Unraveling the molecular mechanism of human polynucleotide phosphorylase (hPNPase) in controlling oxidized RNA.
Creator
Malla, Sulochan, Li, Zhongwei, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Science
Abstract/Description
Oxidation by reactive oxygen species is the major source of RNA damaging insult in living organisms. Increased RNA oxidation has been strongly implicated in a wide range of human diseases; predominantly neurodegeneration. Oxidized RNA should be removed from the cellular system to prevent their deleterious effect to the cells and organisms. In eukaryotic cells, mitochondria are the major intracellular sources of ROS and may cause greater damage to the mitochondrial RNA. In this study, we first...
Show moreOxidation by reactive oxygen species is the major source of RNA damaging insult in living organisms. Increased RNA oxidation has been strongly implicated in a wide range of human diseases; predominantly neurodegeneration. Oxidized RNA should be removed from the cellular system to prevent their deleterious effect to the cells and organisms. In eukaryotic cells, mitochondria are the major intracellular sources of ROS and may cause greater damage to the mitochondrial RNA. In this study, we first investigated the RNA oxidation, by measuring the level of 8-hydroxy-Guanosine (8-oxo-Guo), inside mitochondria and cytoplasm in cultured human cells. We discovered that the mitochondrial 8-oxo-Guo is higher than its cytoplasmic counterparts under both normal growth and oxidative stress condition. Next, we explored the role of human polynucleotide phosphorylase (hPNPase) in controlling RNA oxidation inside mitochondria and cytoplasm. hPNPase binds to oxidized RNA with higher affinity, reduces the 8-oxo-Guo level in total RNA and protects cells against oxidative stress. In this study, the molecular mechanism of hPNPase in 8-oxo-Guo reduction was investigated. First, the effect of hPNPase activities on the 8-oxo-Guo level in mitochondria and cytoplasm was examined. The knockdown of hPNPase increased both the mitochondrial and cytoplasmic 8-oxo-Guo, whereas overexpression had the opposite effect. Second, our study revealed that hSUV3, an RNA helicase that forms a functional complex with hPNPase in mitochondria, was dispensable in reducing 8-oxo-Guo levels.
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Date Issued
2019
PURL
http://purl.flvc.org/fau/fd/FA00013392
Subject Headings
RNA, Reactive Oxygen Species, Mitochondria, Oxidative stress
Format
Document (PDF)
Characterization of RNase in Mycoplasma genitalium and study of its possible role in tRNA processing
Title
Characterization of RNase in Mycoplasma genitalium and study of its possible role in tRNA processing.
Creator
Lalonde, Maureen S., Florida Atlantic University, Li, Zhongwei, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Exoribonucleases degrade RNA and are important in RNA metabolism and gene expression. Mycoplasma genitalium, a bacterium with the smallest genome known, has only one identified exoribonuclease, RNase R (MgR). In this work RNA degradation properties of purified MgR were examined. As observed in Escherichia coli RNase R (EcR) studies, MgR degrades poly(A), rRNA, and oligoribonucleotides in 3'--->5' direction, though its substrate specificity and optimal activity requirements vary. Interestingly...
Show moreExoribonucleases degrade RNA and are important in RNA metabolism and gene expression. Mycoplasma genitalium, a bacterium with the smallest genome known, has only one identified exoribonuclease, RNase R (MgR). In this work RNA degradation properties of purified MgR were examined. As observed in Escherichia coli RNase R (EcR) studies, MgR degrades poly(A), rRNA, and oligoribonucleotides in 3'--->5' direction, though its substrate specificity and optimal activity requirements vary. Interestingly, MgR is sensitive to 2-O-methylation stopping downstream of such modifications in native rRNA and synthetic oligoribonucleotides. MgR removes the 3' trailer sequence from a tRNA precursor of M. genitalium and generates products equal to the mature tRNA, demonstrating a role of MgR in tRNA maturation. The 3' terminal CCA sequence and the acceptor stem of tRNA play a role in determining the formation of such products by MgR. These results suggest multiple functions of RNase R in RNA metabolism in Mycoplasma.
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Date Issued
2006
PURL
http://purl.flvc.org/fcla/dt/13317
Subject Headings
Gene expression, RNA-protein interactions, Cellular control mechanisms, Ribonucleases--Analysis, Cell membranes
Format
Document (PDF)