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Journal articles on the topic 'Molecular Modifications'
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1
Rehpenn, Andreas, Alexandra Walter, and Golo Storch. "Molecular Editing of Flavins for Catalysis." Synthesis 53, no. 15 (March 22, 2021): 2583–93. http://dx.doi.org/10.1055/a-1458-2419.
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AbstractThe diverse activity of flavoenzymes in organic transformations has fascinated researchers for a long time. However, when applied outside an enzyme environment, the isolated flavin cofactor only shows largely reduced activity. This highlights the importance of embedding the reactive isoalloxazine core of flavins in defined surroundings. The latter include crucial non-covalent interactions with amino acid side chains or backbone as well as controlled access to reactants such as molecular oxygen. Nevertheless, molecular flavins are increasingly applied in the organic laboratory as valuable organocatalysts. Chemical modification of the parent isoalloxazine structure is of particular interest in this context in order to achieve reactivity and selectivity in transformations, which are so far only known with flavoenzymes or even unprecedented. This review aims to give a systematic overview of the reported designed flavin catalysts and highlights the impact of each structural alteration. It is intended to serve as a source of information when comparing the performance of known catalysts, but also when designing new flavins. Over the last few decades, molecular flavin catalysis has emerged from proof-of-concept reactions to increasingly sophisticated transformations. This stimulates anticipating new flavin catalyst designs for solving contemporary challenges in organic synthesis.1 Introduction2 N1-Modification3 N3-Modification4 N5-Modification5 C6–C9-Modification6 N10-Modification7 Conclusion
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Li, Yinglu, Zhiming Li, and Wei-Guo Zhu. "Molecular Mechanisms of Epigenetic Regulators as Activatable Targets in Cancer Theranostics." Current Medicinal Chemistry 26, no. 8 (May 16, 2019): 1328–50. http://dx.doi.org/10.2174/0929867324666170921101947.
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Epigenetics is defined as somatically inheritable changes that are not accompanied by alterations in DNA sequence. Epigenetics encompasses DNA methylation, covalent histone modifications, non-coding RNA as well as nucleosome remodeling. Notably, abnormal epigenetic changes play a critical role in cancer development including malignant transformation, metastasis, prognosis, drug resistance and tumor recurrence, which can provide effective targets for cancer prognosis, diagnosis and therapy. Understanding these changes provide effective means for cancer diagnosis and druggable targets for better clinical applications. Histone modifications and related enzymes have been found to correlate well with cancer incidence and prognosis in recent years. Dysregulated expression or mutation of histone modification enzymes and histone modification status abnormalities have been considered to play essential roles in tumorigenesis and clinical outcomes of cancer treatment. Some of the histone modification inhibitors have been extensively employed in clinical practice and many others are still under laboratory research or pre-clinical assessment. Here we summarize the important roles of epigenetics, especially histone modifications in cancer diagnostics and therapeutics, and also discuss the developmental implications of activatable epigenetic targets in cancer theranostics.
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Eichler, Jerry, and Michael W. W. Adams. "Posttranslational Protein Modification in Archaea." Microbiology and Molecular Biology Reviews 69, no. 3 (September 2005): 393–425. http://dx.doi.org/10.1128/mmbr.69.3.393-425.2005.
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SUMMARY One of the first hurdles to be negotiated in the postgenomic era involves the description of the entire protein content of the cell, the proteome. Such efforts are presently complicated by the various posttranslational modifications that proteins can experience, including glycosylation, lipid attachment, phosphorylation, methylation, disulfide bond formation, and proteolytic cleavage. Whereas these and other posttranslational protein modifications have been well characterized in Eucarya and Bacteria, posttranslational modification in Archaea has received far less attention. Although archaeal proteins can undergo posttranslational modifications reminiscent of what their eucaryal and bacterial counterparts experience, examination of archaeal posttranslational modification often reveals aspects not previously observed in the other two domains of life. In some cases, posttranslational modification allows a protein to survive the extreme conditions often encountered by Archaea. The various posttranslational modifications experienced by archaeal proteins, the molecular steps leading to these modifications, and the role played by posttranslational modification in Archaea form the focus of this review.
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Winter, Stefan, and Wolfgang Fischle. "Epigenetic markers and their cross-talk." Essays in Biochemistry 48 (September 20, 2010): 45–61. http://dx.doi.org/10.1042/bse0480045.
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Post-translational modifications of histone proteins in conjunction with DNA methylation represent important events in the regulation of local and global genome functions. Advances in the study of these chromatin modifications established temporal and spatial co-localization of several distinct ‘marks’ on the same histone and/or the same nucleosome. Such complex modification patterns suggest the possibility of combinatorial effects. This idea was originally proposed to establish a code of histone modifications that regulates the interpretation of the genetic code of DNA. Indeed, interdependency of different modifications is now well documented in the literature. Our current understanding is that the function of a given histone modification is influenced by neighbouring or additional modifications. Such context sensitivity of the readout of a modification provides more flexible translation than would be possible if distinct modifications function as isolated units. The mechanistic principles for modification cross-talk can originate in the modulation of the activity of histone-modifying enzymes or may be due to selective recognition of these marks via modification of specific binding proteins. In the present chapter, we discuss fundamental biochemical principles of modification cross-talk and reflect on the interplay of chromatin marks in cellular signalling, cell-cycle progression and cell-fate determination.
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Chukwuma Sr, Chrysanthus. "Characterization of the Clinical and Molecular Perspectives of Epigenetics." Archives of Clinical Investigation 1, no. 1 (October 17, 2022): 01–07. http://dx.doi.org/10.31579/2834-8087/003.
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This review provides the latitude to examine the extant information in the univeral characterizations of epigenetic formulations. Epigenetics encompasses the interaction of behaviours and environment culminating in changes which influence gene activity. In contrast to genetic modifications, epigenetic modifications are reversible; and do not alter the DNA sequence but are capable of interferring in the way the DNA sequence is read. Epigenetic alterations involve genetic changes which effect gene functionality without modifying the underlying DNA sequence. DNA methylation depicts the covalent superimposed methyl group to cytosine in CpG dinucleotides. DNA methylation presents as a veritable epigenetic modification; and it governs gene expression by changing chromosome structure, DNA conformation and stability as well as the function trajectory between DNA and protein. DNA methylation regulates gene expression via the conscription of proteins associated with gene expression or by the inhibition of the binding of transcription factor(s) to DNA. Whereas genetic alterations do modify protein formation, it is clear that epigenetic alterations impact on gene expression to put genes ''on'' and ''off'', as appropriate. The resultant impact of environmental and anthropogenic idiosyncracies, such as diet and physical activity are liable to induce epigenetic modifications in behaviours and gene-environment interactions. Genes are not always in functional mode. DNA methylation constitutes a select epigenetic process applied by cells for the control of gene expression. within the genome. Alterations in gene activity and epigenetic errors can result in varying genetic, metabolic and degenerative disorders which may disparately or in comorbid presentaions influence inter alia health, gene activity or expression, protein production and functionality. This entry exemplifies the reading and understanding of epigenetics in relation to inter alia beneficial developmental theories within the human race.
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Miki, Keishu, Takeshi Watanabe, and Shinji Koh. "Electrochemical Characterization of CVD-Grown Graphene for Designing Electrode/Biomolecule Interfaces." Crystals 10, no. 4 (March 26, 2020): 241. http://dx.doi.org/10.3390/cryst10040241.
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In research on enzyme-based biofuel cells, covalent or noncovalent molecular modifications of carbon-based electrode materials are generally used as a method for immobilizing enzymes and/or mediators. However, the influence of these molecular modifications on the electrochemical properties of electrode materials has not been clarified. In this study, we present the electrochemical properties of chemical vapor deposition (CVD)-grown monolayer graphene electrodes before and after molecular modification. The electrochemical properties of graphene electrodes were evaluated by cyclic voltammetry and electrochemical impedance measurements. A covalently modified graphene electrode showed an approximately 25-fold higher charge transfer resistance than before modification. In comparison, the electrochemical properties of a noncovalently modified graphene electrode were not degraded by the modification.
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Wang, Ya-Nan, Chen-Yang Yu, and Hong-Zhong Jin. "RNA N6-Methyladenosine Modifications and the Immune Response." Journal of Immunology Research 2020 (January 21, 2020): 1–6. http://dx.doi.org/10.1155/2020/6327614.
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N6-methyladenosine (m6A) is the most important modification of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in higher eukaryotes. Modulation of m6A modifications relies on methyltransferases and demethylases. The discovery of binding proteins confirms that the m6A modification has a wide range of biological effects and significance at the molecular, cellular, and physiological levels. In recent years, techniques for investigating m6A modifications of RNA have developed rapidly. This article reviews the biological significance of RNA m6A modifications in the innate immune response, adaptive immune response, and viral infection.
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Han, Dali, and Meng Michelle Xu. "RNA Modification in the Immune System." Annual Review of Immunology 41, no. 1 (April 26, 2023): 73–98. http://dx.doi.org/10.1146/annurev-immunol-101921-045401.
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Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in RNA modification on various forms of RNA are essential for the development and function of the immune system. In this review, we discuss the value of innovative RNA modification profiling technologies to uncover the function of these diverse, dynamic RNA modifications in various immune cells within healthy and diseased contexts. Further, we explore our current understanding of the mechanisms whereby aberrant RNA modifications modulate the immune milieu of the tumor microenvironment and point out outstanding research questions.
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Wölk, Michele, Theres Schröter, Ralf Hoffmann, and Sanja Milkovska-Stamenova. "Profiling of Low-Molecular-Weight Carbonyls and Protein Modifications in Flavored Milk." Antioxidants 9, no. 11 (November 23, 2020): 1169. http://dx.doi.org/10.3390/antiox9111169.
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Thermal treatments of dairy products favor oxidations, Maillard reactions, and the formation of sugar or lipid oxidation products. Additives including flavorings might enhance these reactions or even induce further reactions. Here we aimed to characterize protein modifications in four flavored milk drinks using samples along the production chain—raw milk, pasteurization, mixing with flavorings, heat treatment, and the commercial product. Therefore, milk samples were analyzed using a bottom up proteomics approach and a combination of data-independent (MSE) and data-dependent acquisition methods (DDA). Twenty-one small carbonylated lipids were identified by shotgun lipidomics triggering 13 protein modifications. Additionally, two Amadori products, 12 advanced glycation end products (AGEs), and 12 oxidation-related modifications were targeted at the protein level. The most common modifications were lactosylation, formylation, and carboxymethylation. The numbers and distribution of modification sites present in raw milk remained stable after pasteurization and mixing with flavorings, while the final heat treatment significantly increased lactosylation and hexosylation in qualitative and quantitative terms. The processing steps did not significantly affect the numbers of AGE-modified, oxidized/carbonylated, and lipid-carbonylated sites in proteins.
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Ogihara, Takuo, Kenta Mizoi, and Akiko Ishii-Watabe. "Pharmacokinetics of Biopharmaceuticals: Their Critical Role in Molecular Design." Biomedicines 11, no. 5 (May 16, 2023): 1456. http://dx.doi.org/10.3390/biomedicines11051456.
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Biopharmaceuticals have developed rapidly in recent years due to the remarkable progress in gene recombination and cell culture technologies. Since the basic structure of biopharmaceuticals can be designed and modified, it is possible to control the duration of action and target specific tissues and cells by kinetic modification. Amino acid sequence modifications, albumin fusion proteins, polyethylene glycol (PEG) modifications, and fatty acid modifications have been utilized to modify the duration of action control and targeting. This review first describes the position of biopharmaceuticals, and then the kinetics (absorption, distribution, metabolism, elimination, and pharmacokinetics) of classical biopharmaceuticals and methods of drug quantification. The kinetic innovations of biopharmaceuticals are outlined, including insulin analog, antibody-related drugs (monoclonal antibodies, Fab analogs, Fc analogs, Fab-PEG conjugated proteins, antibody-drug conjugates, etc.), blood coagulation factors, interferons, and other related drugs. We hope that this review will be of use to many researchers interested in pharmaceuticals derived from biological components, and that it aids in their knowledge of the latest developments in this field.
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Luo, Danzhi, Xiaohong Li, Simin Tang, Fuhu Song, Wenjun Li, Guiling Xie, Jinshu Liang, and Jun Zhou. "Epigenetic modifications in neuropathic pain." Molecular Pain 17 (January 2021): 174480692110567. http://dx.doi.org/10.1177/17448069211056767.
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Neuropathic pain (NP) is a common symptom in many diseases of the somatosensory nervous system, which severely affects the patient’s quality of life. Epigenetics are heritable alterations in gene expression that do not cause permanent changes in the DNA sequence. Epigenetic modifications can affect gene expression and function and can also mediate crosstalk between genes and the environment. Increasing evidence shows that epigenetic modifications, including DNA methylation, histone modification, non-coding RNA, and RNA modification, are involved in the development and maintenance of NP. In this review, we focus on the current knowledge of epigenetic modifications in the development and maintenance of NP. Then, we illustrate different facets of epigenetic modifications that regulate gene expression and their crosstalk. Finally, we discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies, which has been valuable in understanding mechanisms and offers novel and potent targets for NP therapy.
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Carson, Spencer, James Wilson, Aleksei Aksimentiev, Peter R. Weigele, and Meni Wanunu. "Hydroxymethyluracil modifications enhance the flexibility and hydrophilicity of double-stranded DNA." Nucleic Acids Research 44, no. 5 (November 17, 2015): 2085–92. http://dx.doi.org/10.1093/nar/gkv1199.
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Abstract Oxidation of a DNA thymine to 5-hydroxymethyluracil is one of several recently discovered epigenetic modifications. Here, we report the results of nanopore translocation experiments and molecular dynamics simulations that provide insight into the impact of this modification on the structure and dynamics of DNA. When transported through ultrathin solid-state nanopores, short DNA fragments containing thymine modifications were found to exhibit distinct, reproducible features in their transport characteristics that differentiate them from unmodified molecules. Molecular dynamics simulations suggest that 5-hydroxymethyluracil alters the flexibility and hydrophilicity of the DNA molecules, which may account for the differences observed in our nanopore translocation experiments. The altered physico-chemical properties of DNA produced by the thymine modifications may have implications for recognition and processing of such modifications by regulatory DNA-binding proteins.
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Estevez, Mariana, Rui Li, Biplab Paul, Kaveh Daneshvar, Alan C. Mullen, Fabio Romerio, and Balasubrahmanyam Addepalli. "Identification and mapping of post-transcriptional modifications on the HIV-1 antisense transcript Ast in human cells." RNA 28, no. 5 (February 15, 2022): 697–710. http://dx.doi.org/10.1261/rna.079043.121.
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The human immunodeficiency virus type 1 (HIV-1) encodes multiple RNA molecules. Transcripts that originate from the proviral 5′ long terminal repeat (LTR) function as messenger RNAs for the expression of 16 different mature viral proteins. In addition, HIV-1 expresses an antisense transcript (Ast) from the 3′LTR, which has both protein-coding and noncoding properties. While the mechanisms that regulate the coding and noncoding activities of Ast remain unknown, post-transcriptional modifications are known to influence RNA stability, interaction with protein partners, and translation capacity. Here, we report the nucleoside modification profile of Ast obtained through liquid chromatography coupled with mass spectrometry (LC-MS) analysis. The epitranscriptome includes a limited set of modified nucleosides but predominantly ribose methylations. A number of these modifications were mapped to specific positions of the sequence through RNA modification mapping procedures. The presence of modifications on Ast is consistent with the RNA-modifying enzymes interacting with Ast. The identification and mapping of Ast post-transcriptional modifications is expected to elucidate the mechanisms through which this versatile molecule can carry out diverse activities in different cell compartments. Manipulation of post-transcriptional modifications on the Ast RNA may have therapeutic implications.
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He, Ruidi, Songnan Li, Gongqi Zhao, Ligong Zhai, Peng Qin, and Liping Yang. "Starch Modification with Molecular Transformation, Physicochemical Characteristics, and Industrial Usability: A State-of-the-Art Review." Polymers 15, no. 13 (July 3, 2023): 2935. http://dx.doi.org/10.3390/polym15132935.
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Starch is a readily available and abundant source of biological raw materials and is widely used in the food, medical, and textile industries. However, native starch with insufficient functionality limits its utilization in the above applications; therefore, it is modified through various physical, chemical, enzymatic, genetic and multiple modifications. This review summarized the relationship between structural changes and functional properties of starch subjected to different modified methods, including hydrothermal treatment, microwave, pre-gelatinization, ball milling, ultrasonication, radiation, high hydrostatic pressure, supercritical CO2, oxidation, etherification, esterification, acid hydrolysis, enzymatic modification, genetic modification, and their combined modifications. A better understanding of these features has the potential to lead to starch-based products with targeted structures and optimized properties for specific applications.
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Valadon, Charlène, and Olivier Namy. "The Importance of the Epi-Transcriptome in Translation Fidelity." Non-Coding RNA 7, no. 3 (August 27, 2021): 51. http://dx.doi.org/10.3390/ncrna7030051.
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RNA modifications play an essential role in determining RNA fate. Recent studies have revealed the effects of such modifications on all steps of RNA metabolism. These modifications range from the addition of simple groups, such as methyl groups, to the addition of highly complex structures, such as sugars. Their consequences for translation fidelity are not always well documented. Unlike the well-known m6A modification, they are thought to have direct effects on either the folding of the molecule or the ability of tRNAs to bind their codons. Here we describe how modifications found in tRNAs anticodon-loop, rRNA, and mRNA can affect translation fidelity, and how approaches based on direct manipulations of the level of RNA modification could potentially be used to modulate translation for the treatment of human genetic diseases.
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Kao, Robert M., Yan Liu, and Jihong Bai. "Doing the Molecular Splits: Hands-On Demonstration Tips to Promote Student Engagement Using Split Inteins in Molecular Biology." American Biology Teacher 82, no. 7 (September 1, 2020): 499–502. http://dx.doi.org/10.1525/abt.2020.82.7.499.
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Engaging undergraduates in the mechanisms of post-translational modifications lies at the heart of molecular and cell biology education. An important challenge for science educators is developing inclusive and equitable approaches and hands-on demonstrations to clarify post-translational modification mechanisms, such as the protein-splicing mechanism called split inteins. Here, we describe step-by-step assembly of recycled materials to help clarify the molecular action of split inteins in inclusive classroom teaching settings.
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Jeltsch, Albert, Julian Broche, and Pavel Bashtrykov. "Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes." Genes 9, no. 11 (November 21, 2018): 566. http://dx.doi.org/10.3390/genes9110566.
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DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs) in the case of DNA methylation, are directly or indirectly targeted and regulated by other marks. Here, we have collected information about the genomic distribution and variability of DNA methylation in human and mouse DNA in different genomic elements. After summarizing the impact of DNA methylation on genome evolution including CpG depletion, we describe the connection of DNA methylation with several important histone post-translational modifications, including methylation of H3K4, H3K9, H3K27, and H3K36, but also with nucleosome remodeling. Moreover, we present the mechanistic features of mammalian DNA methyltransferases and their associated factors that mediate the crosstalk between DNA methylation and chromatin modifications. Finally, we describe recent advances regarding the methylation of non-CpG sites, methylation of adenine residues in human cells and methylation of mitochondrial DNA. At several places, we highlight controversial findings or open questions demanding future experimental work.
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Leseva, Milena N., Brigitta Buttari, Luciano Saso, and Petya A. Dimitrova. "Infection Meets Inflammation: N6-Methyladenosine, an Internal Messenger RNA Modification as a Tool for Pharmacological Regulation of Host–Pathogen Interactions." Biomolecules 13, no. 7 (June 29, 2023): 1060. http://dx.doi.org/10.3390/biom13071060.
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The significance of internal mRNA modifications for the modulation of transcript stability, for regulation of nuclear export and translation efficiency, and their role in suppressing innate immunity is well documented. Over the years, the molecular complexes involved in the dynamic regulation of the most prevalent modifications have been characterized—we have a growing understanding of how each modification is set and erased, where it is placed, and in response to what cues. Remarkably, internal mRNA modifications, such as methylation, are emerging as an additional layer of regulation of immune cell homeostasis, differentiation, and function. A fascinating recent development is the investigation into the internal modifications of host/pathogen RNA, specifically N6-methyladenosine (m6A), its abundance and distribution during infection, and its role in disease pathogenesis and in shaping host immune responses. Low molecular weight compounds that target RNA-modifying enzymes have shown promising results in vitro and in animal models of different cancers and are expanding the tool-box in immuno-oncology. Excitingly, such modulators of host mRNA methyltransferase or demethylase activity hold profound implications for the development of new broad-spectrum therapeutic agents for infectious diseases as well. This review describes the newly uncovered role of internal mRNA modification in infection and in shaping the function of the immune system in response to invading pathogens. We will also discuss its potential as a therapeutic target and identify pitfalls that need to be overcome if it is to be effectively leveraged against infectious agents.
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Hawer, Harmen, Alexander Hammermeister, Keerthiraju Ravichandran, Sebastian Glatt, Raffael Schaffrath, and Roland Klassen. "Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer." Genes 10, no. 1 (December 28, 2018): 19. http://dx.doi.org/10.3390/genes10010019.
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Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.
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Rabany, Ofri, and Daphna Nachmani. "Small Nucleolar (Sno)RNA: Therapy Lays in Translation." Non-Coding RNA 9, no. 3 (June 8, 2023): 35. http://dx.doi.org/10.3390/ncrna9030035.
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The ribosome is one of the largest complexes in the cell. Adding to its complexity are more than 200 RNA modification sites present on ribosomal RNAs (rRNAs) in a single human ribosome. These modifications occur in functionally important regions of the rRNA molecule, and they are vital for ribosome function and proper gene expression. Until recent technological advancements, the study of rRNA modifications and their profiles has been extremely laborious, leaving many questions unanswered. Small nucleolar RNAs (snoRNAs) are non-coding RNAs that facilitate and dictate the specificity of rRNA modification deposition, making them an attractive target for ribosome modulation. Here, we propose that through the mapping of rRNA modification profiles, we can identify cell-specific modifications with high therapeutic potential. We also describe the challenges of achieving the targeting specificity needed to implement snoRNAs as therapeutic targets in cancers.
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Ontiveros, R. Jordan, Julian Stoute, and Kathy Fange Liu. "The chemical diversity of RNA modifications." Biochemical Journal 476, no. 8 (April 26, 2019): 1227–45. http://dx.doi.org/10.1042/bcj20180445.
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AbstractNucleic acid modifications in DNA and RNA ubiquitously exist among all the three kingdoms of life. This trait significantly broadens the genome diversity and works as an important means of gene transcription regulation. Although mammalian systems have limited types of DNA modifications, over 150 different RNA modification types have been identified, with a wide variety of chemical diversities. Most modifications occur on transfer RNA and ribosomal RNA, however many of the modifications also occur on other types of RNA species including mammalian mRNA and small nuclear RNA, where they are essential for many biological roles, including developmental processes and stem cell differentiation. These post-transcriptional modifications are enzymatically installed and removed in a site-specific manner by writer and eraser proteins respectively, while reader proteins can interpret modifications and transduce the signal for downstream functions. Dysregulation of mRNA modifications manifests as disease states, including multiple types of human cancer. In this review, we will introduce the chemical features and biological functions of these modifications in the coding and non-coding RNA species.
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Noon, Kathleen R., Rebecca Guymon, Pamela F. Crain, James A. McCloskey, Michael Thomm, Julianne Lim, and Ricardo Cavicchioli. "Influence of Temperature on tRNA Modification in Archaea: Methanococcoides burtonii (Optimum Growth Temperature [Topt], 23°C) and Stetteria hydrogenophila (Topt, 95°C)." Journal of Bacteriology 185, no. 18 (September 15, 2003): 5483–90. http://dx.doi.org/10.1128/jb.185.18.5483-5490.2003.
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ABSTRACT We report the first study of tRNA modification in psychrotolerant archaea, specifically in the archaeon Methanococcoides burtonii grown at 4 and 23°C. For comparison, unfractionated tRNA from the archaeal hyperthermophile Stetteria hydrogenophila cultured at 93°C was examined. Analysis of modified nucleosides using liquid chromatography-electrospray ionization mass spectrometry revealed striking differences in levels and identities of tRNA modifications between the two organisms. Although the modification levels in M. burtonii tRNA are the lowest in any organism of which we are aware, it contains more than one residue per tRNA molecule of dihydrouridine, a molecule associated with maintenance of polynucleotide flexibility at low temperatures. No differences in either identities or levels of modifications, including dihydrouridine, as a function of culture temperature were observed, in contrast to selected tRNA modifications previously reported for archaeal hyperthermophiles. By contrast, S. hydrogenophila tRNA was found to contain a remarkable structural diversity of 31 modified nucleosides, including nine methylated guanosines, with eight different nucleoside species methylated at O-2′ of ribose, known to be an effective stabilizing motif in RNA. These results show that some aspects of tRNA modification in archaea are strongly associated with environmental temperature and support the thesis that posttranscriptional modification is a universal natural mechanism for control of RNA molecular structure that operates across a wide temperature range in archaea as well as bacteria.
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Jo, Chanhee, Seokjae Park, Sungjoon Oh, Jinmi Choi, Eun-Kyoung Kim, Hong-Duk Youn, and Eun-Jung Cho. "Histone acylation marks respond to metabolic perturbations and enable cellular adaptation." Experimental & Molecular Medicine 52, no. 12 (December 2020): 2005–19. http://dx.doi.org/10.1038/s12276-020-00539-x.
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AbstractAcetylation is the most studied histone acyl modification and has been recognized as a fundamental player in metabolic gene regulation, whereas other short-chain acyl modifications have only been recently identified, and little is known about their dynamics or molecular functions at the intersection of metabolism and epigenetic gene regulation. In this study, we aimed to understand the link between nonacetyl histone acyl modification, metabolic transcriptional regulation, and cellular adaptation. Using antibodies specific for butyrylated, propionylated, and crotonylated H3K23, we analyzed dynamic changes of H3K23 acylation upon various metabolic challenges. Here, we show that H3K23 modifications were highly responsive and reversibly regulated by nutrient availability. These modifications were commonly downregulated by the depletion of glucose and recovered based on glucose or fatty acid availability. Depletion of metabolic enzymes, namely, ATP citrate lyase, carnitine acetyltransferase, and acetyl-CoA synthetase, which are involved in Ac-CoA synthesis, resulted in global loss of H3K23 butyrylation, crotonylation, propionylation, and acetylation, with a profound impact on gene expression and cellular metabolic states. Our data indicate that Ac-CoA/CoA and central metabolic inputs are important for the maintenance of histone acylation. Additionally, genome-wide analysis revealed that acyl modifications are associated with gene activation. Our study shows that histone acylation acts as an immediate and reversible metabolic sensor enabling cellular adaptation to metabolic stress by reprogramming gene expression.
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Bohnsack, Markus T., and Katherine E. Sloan. "Modifications in small nuclear RNAs and their roles in spliceosome assembly and function." Biological Chemistry 399, no. 11 (October 25, 2018): 1265–76. http://dx.doi.org/10.1515/hsz-2018-0205.
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Abstract Modifications in cellular RNAs have emerged as key regulators of all aspects of gene expression, including pre-mRNA splicing. During spliceosome assembly and function, the small nuclear RNAs (snRNAs) form numerous dynamic RNA-RNA and RNA-protein interactions, which are required for spliceosome assembly, correct positioning of the spliceosome on substrate pre-mRNAs and catalysis. The human snRNAs contain several base methylations as well as a myriad of pseudouridines and 2′-O-methylated nucleotides, which are largely introduced by small Cajal body-specific ribonucleoproteins (scaRNPs). Modified nucleotides typically cluster in functionally important regions of the snRNAs, suggesting that their presence could optimise the interactions of snRNAs with each other or with pre-mRNAs, or may affect the binding of spliceosomal proteins. snRNA modifications appear to play important roles in snRNP biogenesis and spliceosome assembly, and have also been proposed to influence the efficiency and fidelity of pre-mRNA splicing. Interestingly, alterations in the modification status of snRNAs have recently been observed in different cellular conditions, implying that some snRNA modifications are dynamic and raising the possibility that these modifications may fine-tune the spliceosome for particular functions. Here, we review the current knowledge on the snRNA modification machinery and discuss the timing, functions and dynamics of modifications in snRNAs.
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Seto, E. "Histone modifications." Methods 31, no. 1 (September 2003): 1–2. http://dx.doi.org/10.1016/s1046-2023(03)00081-1.
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Chiu, Norman H., Jennifer H. Simpson, Renata L. Fleming, Jian Teng, and Bakhos A. Tannous. "Abstract LB507: Towards elucidating the role of RNA modifications in cancer by improving the quantitative accuracy of mass spectrometric profiling of RNA modifications." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB507. http://dx.doi.org/10.1158/1538-7445.am2022-lb507.
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Abstract The molecular structure of both coding and non-coding RNA is frequently altered by the enzymatic activity of either writer or eraser of RNA modifications. Since the RNA functions are dependent on its molecular structure, cellular activities that involve specific RNA molecule(s) can potentially be regulated by the reversible nature of RNA modifications. There are more than 140 known RNA modifications. Mass spectrometry is a proven technique for the identification of RNA modifications. However, due to the lack of ribonucleoside standards and biases in normalizing the level of RNA modifications, it remains a challenge to perform the quantitative analysis of multiple RNA modifications that may co-exist in a biological sample. Our group has recently developed a method for standard-free quantitative epitranscriptomic profiling (SqEP) that allows us using mass spectrometry to accurately determine the abundancy of each detectable RNA modification without using any ribonucleoside standards to calibrate the detection signals. Thus, the SqEP method can be used for the untargeted analysis of RNA modifications. It also allows us to directly compare the level of different RNA modifications that are detectable in an individual cell line. This is an important feature for studying the relationships between various RNA modifications. Using glioblastoma (GBM) as our model, the results from using the SqEP method to determine the level of specific RNA modifications in patient-derived GBM cell lines were shown to be more accurate than the existing methods, and complied with the gene expression data from GBM patients that are available in the Cancer Genome Atlas (TCGA) program. Citation Format: Norman H. Chiu, Jennifer H. Simpson, Renata L. Fleming, Jian Teng, Bakhos A. Tannous. Towards elucidating the role of RNA modifications in cancer by improving the quantitative accuracy of mass spectrometric profiling of RNA modifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB507.
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Tafeenko, V. A., V. V. Chernyshev, A. V. Yatsenko, V. A. Makarov, E. J. Sonneveld, R. Peschar, and H. Schenk. "Intermolecular —CH3...O2N— contacts in two polymorphic modifications of (1E)-N'-[(E)-2-cyano-1-(dimethylamino)-2-nitrovinyl]-N,N-dimethylethanimidamide." Acta Crystallographica Section B Structural Science 59, no. 4 (July 25, 2003): 492–97. http://dx.doi.org/10.1107/s0108768103010231.
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The title compound was synthesized and isolated in two crystal modifications. The structure of the orthorhombic modification was determined by the X-ray powder diffraction method and the structure of the monoclinic modification was determined using the X-ray single-crystal diffraction technique. The molecules in both polymorphs are E,E isomers. Intermolecular H3C...NO2 contacts and their role in the formation of the polymorphic modifications are analyzed.
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A. Alemu, Endalkachew, Chuan He, and Arne Klungland. "ALKBHs-facilitated RNA modifications and de-modifications." DNA Repair 44 (August 2016): 87–91. http://dx.doi.org/10.1016/j.dnarep.2016.05.026.
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Huang, Chang, Mo Xu, and Bing Zhu. "Epigenetic inheritance mediated by histone lysine methylation: maintaining transcriptional states without the precise restoration of marks?" Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1609 (January 5, 2013): 20110332. http://dx.doi.org/10.1098/rstb.2011.0332.
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‘Epigenetics’ has been defined as the study of ‘mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence’. Chromatin modifications are major carriers of epigenetic information that both reflect and affect the transcriptional states of underlying genes. Several histone modifications are key players that are responsible for classical epigenetic phenomena. However, the mechanisms by which cells pass their histone modifications to daughter cells through mitotic division remain to be unveiled. Here, we review recent progress in the field and conclude that epigenetic modifications are not precisely maintained at a near-mononucleosome level of precision. We also suggest that transcription repression may be maintained by a buffer system that can tolerate a certain degree of fluctuation in repressive histone modification levels. This buffer system protects the repressed genes from potential improper derepression triggered by chromatin modification-level fluctuation resulting from cellular events, such as the cell-cycle-dependent dilution of the chromatin modifications and local responses to environmental cues.
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Bayer, E. A., H. Ben-Hur, Y. Hiller, and M. Wilchek. "Postsecretory modifications of streptavidin." Biochemical Journal 259, no. 2 (April 15, 1989): 369–76. http://dx.doi.org/10.1042/bj2590369.
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Streptavidin, an extracellular biotin-binding protein from Streptomyces avidinii, exhibits a multiplicity in its electrophoretic mobility pattern which depends both upon the conditions for growth of the bacterium and upon the protocol used in the purification of the protein. The observed structural heterogeneity appears to reflect the action of two types of postsecretory molecular events: proteolytic digestion of the intact Mr-18,000 subunit to a minimal molecular size (approx. Mr 14,000), and aggregation of the native tetramer into higher-order oligomeric forms. The extent of subunit degradation and/or tetrameric aggregation affects the capacity of a given streptavidin preparation to interact with biotin-conjugated proteins in different assay systems.
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Xue, Hong, Yilong Xue, Sylvie Doublié, and Charles W. Carter, Jr. "Chemical modifications of Bacillus subtilis tryptophanyl-tRNA synthetase." Biochemistry and Cell Biology 75, no. 6 (December 1, 1997): 709–15. http://dx.doi.org/10.1139/o97-054.
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A concerted conformational change in Bacillus subtilis tryptophanyl-tRNA synthetase (TrpRS) was evident from previous fluorescence on the quenching of the single Trp residue Trp-92 in the 4FTrp-AMP complexed enzyme. In this study, chemical modifications of the B. subtilis TrpRS were employed to further characterize this conformational change, with the single Trp residue serving as a marker for monitoring the change. Modifications of the enzyme by means of the Trp-specific agent N-bromosuccinimide (NBS) or 3-bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole (BNPS-skatole) inactivated the enzyme in accord with the essential role of Trp-92, as identified previously by site-directed mutagenesis. ATP sensitized TrpRS toward inactivation by NBS and BNPS-skatole, which suggested a conformational change that resulted in greater accessibility of Trp-92 toward modifications. In contrast, the cognate tRNATrp substrate exerted a specific protective effect against inactivation by both of the reagents, indicating that the TrpRS-tRNATrp interaction reduces the accessibility of Trp-92 under our experimental conditions. By comparison, modification of sulfhydryl groups by means of iodoacetamide did not reduce TrpRS activity. Observations on Trp-specific modification and substrate protection effects are discussed in the context of the Bacillus stearothermophilus TrpRS crystal structure. Key words: aminoacyl-tRNA synthetase, Bacillus subtilis, chemical modification, conformational change, transfer RNA, tryptophanyl-tRNA synthetase.
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Hili, Ryan, Chun Guo, Dehui Kong, and Yi Lei. "Expanding the Chemical Diversity of DNA." Synlett 29, no. 11 (March 20, 2018): 1405–14. http://dx.doi.org/10.1055/s-0036-1591959.
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Nucleic acid polymers can be evolved to exhibit desired properties, including molecular recognition of a molecular target and catalysis of a specific reaction. These properties can be readily evolved despite the dearth of chemical diversity available to nucleic acid polymers, especially when compared to the rich chemical complexity of proteins. Expansion of nucleic acid chemical diversity has therefore been an important thrust for improving their properties for analytical and biomedical applications. Herein, we briefly describe the current state-of-the-art for the sequence-defined incorporation of modifications throughout an evolvable nucleic acid polymer. This includes contributions from our own lab, which have expanded the chemical diversity of nucleic acid polymers closer to the level observed in proteinogenic polymers.1 Introduction2 Polymerase-Catalyzed Synthesis of Modified Nucleic Acid Polymers3 Ligase-Catalyzed Oligonucleotide Polymerization (LOOPER)4 LOOPER with Small Modifications5 LOOPER with Large Modifications6 Evolution of Aptamers Derived from LOOPER Libraries7 Outlook
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Deryusheva, Svetlana, Gaëlle J. S. Talhouarne, and Joseph G. Gall. "“Lost and Found”: snoRNA Annotation in the Xenopus Genome and Implications for Evolutionary Studies." Molecular Biology and Evolution 37, no. 1 (September 6, 2019): 149–66. http://dx.doi.org/10.1093/molbev/msz209.
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Abstract Small nucleolar RNAs (snoRNAs) function primarily as guide RNAs for posttranscriptional modification of rRNAs and spliceosomal snRNAs, both of which are functionally important and evolutionarily conserved molecules. It is commonly believed that snoRNAs and the modifications they mediate are highly conserved across species. However, most relevant data on snoRNA annotation and RNA modification are limited to studies on human and yeast. Here, we used RNA-sequencing data from the giant oocyte nucleus of the frog Xenopus tropicalis to annotate a nearly complete set of snoRNAs. We compared the frog data with snoRNA sets from human and other vertebrate genomes, including mammals, birds, reptiles, and fish. We identified many Xenopus-specific (or nonhuman) snoRNAs and Xenopus-specific domains in snoRNAs from conserved RNA families. We predicted that some of these nonhuman snoRNAs and domains mediate modifications at unexpected positions in rRNAs and snRNAs. These modifications were mapped as predicted when RNA modification assays were applied to RNA from nine vertebrate species: frogs X. tropicalis and X. laevis, newt Notophthalmus viridescens, axolotl Ambystoma mexicanum, whiptail lizard Aspidoscelis neomexicana, zebrafish Danio rerio, chicken, mouse, and human. This analysis revealed that only a subset of RNA modifications is evolutionarily conserved and that modification patterns may vary even between closely related species. We speculate that each functional domain in snoRNAs (half of an snoRNA) may evolve independently and shuffle between different snoRNAs.
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Baubec, Tuncay, and Pierre-Antoine Defossez. "Reading DNA Modifications." Journal of Molecular Biology 432, no. 6 (March 2020): 1599–601. http://dx.doi.org/10.1016/j.jmb.2020.02.001.
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Yang, Weiwei, Alexey Fomenkov, Dan Heiter, Shuang-yong Xu, and Laurence Ettwiller. "High-throughput sequencing of EcoWI restriction fragments maps the genome-wide landscape of phosphorothioate modification at base resolution." PLOS Genetics 18, no. 9 (September 19, 2022): e1010389. http://dx.doi.org/10.1371/journal.pgen.1010389.
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Phosphorothioation (PT), in which a non-bridging oxygen is replaced by a sulfur, is one of the rare modifications discovered in bacteria and archaea that occurs on the sugar-phosphate backbone as opposed to the nucleobase moiety of DNA. While PT modification is widespread in the prokaryotic kingdom, how PT modifications are distributed in the genomes and their exact roles in the cell remain to be defined. In this study, we developed a simple and convenient technique called EcoWI-seq based on a modification-dependent restriction endonuclease to identify genomic positions of PT modifications. EcoWI-seq shows similar performance than other PT modification detection techniques and additionally, is easily scalable while requiring little starting material. As a proof of principle, we applied EcoWI-seq to map the PT modifications at base resolution in the genomes of both the Salmonella enterica cerro 87 and E. coli expressing the dnd+ gene cluster. Specifically, we address whether the partial establishment of modified PT positions is a stochastic or deterministic process. EcoWI-seq reveals a systematic usage of the same subset of target sites in clones for which the PT modification has been independently established.
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Zhu, Yusha, and Max Costa. "Metals and molecular carcinogenesis." Carcinogenesis 41, no. 9 (July 17, 2020): 1161–72. http://dx.doi.org/10.1093/carcin/bgaa076.
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Abstract Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and environmental contaminations in drinking water, air pollution and foods, which can result in serious health problems such as cancer. Arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr) and nickel (Ni) are classified as Group 1 carcinogens by the International Agency for Research on Cancer. This review provides a comprehensive summary of current concepts of the molecular mechanisms of metal-induced carcinogenesis and focusing on a variety of pathways, including genotoxicity, mutagenesis, oxidative stress, epigenetic modifications such as DNA methylation, histone post-translational modification and alteration in microRNA regulation, competition with essential metal ions and cancer-related signaling pathways. This review takes a broader perspective and aims to assist in guiding future research with respect to the prevention and therapy of metal exposure in human diseases including cancer.
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Magistrati, Martina, Alexandru Ionut Gilea, Camilla Ceccatelli Ceccatelli Berti, Enrico Baruffini, and Cristina Dallabona. "Modopathies Caused by Mutations in Genes Encoding for Mitochondrial RNA Modifying Enzymes: Molecular Mechanisms and Yeast Disease Models." International Journal of Molecular Sciences 24, no. 3 (January 22, 2023): 2178. http://dx.doi.org/10.3390/ijms24032178.
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In eukaryotes, mitochondrial RNAs (mt-tRNAs and mt-rRNAs) are subject to specific nucleotide modifications, which are critical for distinct functions linked to the synthesis of mitochondrial proteins encoded by mitochondrial genes, and thus for oxidative phosphorylation. In recent years, mutations in genes encoding for mt-RNAs modifying enzymes have been identified as being causative of primary mitochondrial diseases, which have been called modopathies. These latter pathologies can be caused by mutations in genes involved in the modification either of tRNAs or of rRNAs, resulting in the absence of/decrease in a specific nucleotide modification and thus on the impairment of the efficiency or the accuracy of the mitochondrial protein synthesis. Most of these mutations are sporadic or private, thus it is fundamental that their pathogenicity is confirmed through the use of a model system. This review will focus on the activity of genes that, when mutated, are associated with modopathies, on the molecular mechanisms through which the enzymes introduce the nucleotide modifications, on the pathological phenotypes associated with mutations in these genes and on the contribution of the yeast Saccharomyces cerevisiae to confirming the pathogenicity of novel mutations and, in some cases, for defining the molecular defects.
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Kazuhito, Tomizawa, and Fan-Yan Wei. "Posttranscriptional modifications in mitochondrial tRNA and its implication in mitochondrial translation and disease." Journal of Biochemistry 168, no. 5 (August 20, 2020): 435–44. http://dx.doi.org/10.1093/jb/mvaa098.
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Abstract A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.
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Okada, Naoya, Ryohei Eto, Emi Horiguchi-Babamoto, and Shinya Matsumoto. "Optical Properties of Three Crystal Modifications of a 2,3-Dicyanopyrazine Dye." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C664. http://dx.doi.org/10.1107/s2053273314093358.
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Some pyrazine dyes are known to display strong fluorescence not only in solution but also in the solid-state. 5-t-Butyl-2,3-dicyano-6-[4-(dimethylamino)styryl]pyrazine (1) is a 2,3-dicyanopyrazine dye synthesized for an examination of substituent effects on thin-film growth [1]. Dye 1 was found to exhibit three crystal modifications with different color appearance (I: red, II: black, III: reddish purple). Modification I is a solvate crystal including one chloroform per one dye molecule [2], and modifications II and III are polymorphs. In this work, optical properties of these three modifications were interpreted on the basis of their crystal structures. The absorption spectra of the modifications were measured using optical waveguide spectroscopy. The absorption maxima of modifications I, II and III were found at 559 nm, 462 nm and 571 nm, respectively. A bathochromic absorption shift of reddish modifications I and III from that of 1 in toluene was 79 nm (-2944 cm-1) and 91 nm (-3320 cm-1), respectively. On the other hand, a hypsochromic absorption shift of 18 nm (812 cm-1) was observed in modification II. The fluorescence maxima of modifications I, II and III were found at 619 nm, 734 nm and 668 nm, respectively. The energy displacement corresponding to the observed spectral shifts was characterized in terms of an exciton interaction. The exciton interaction for a dimer was estimated using the extended dipole model, and the nearest-neighbor approximation was applied for evaluating a total energy displacement due to crystallization. The calculation results were qualitatively in good agreement with the observed spectral shifts. The result also revealed that molecular pairs in two-dimensional stacking structure in these modifications play a significant role in the total energy displacement.
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Menon, P., and M. S. Kumar. "DIABETES-POST-TRANSLATIONAL PROTEIN MODIFICATION FOR DEVELOPMENT OF NEW DRUGS." INDIAN DRUGS 51, no. 09 (September 28, 2014): 5–11. http://dx.doi.org/10.53879/id.51.09.p0005.
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Diabetes is a disorder associated with improper use of glucose by the body leading to increased level of glucose in the blood stream. Beta cells in the pancreas produce the hormone insulin, which is responsible for the movement of glucose into cells where it is utilized to produce energy. Due to the shortage of insulin in diabetic condition, the level of glucose in the bloodstream increases. The level of glucose within cells fall and thus the cells are not able to produce energy using glucose. It also gives rise to various other complications such as blindness, kidney failure, numbness in toes, delayed wound healing, cardiovascular complications, weight gain, loss of consciousness, disorientation etc. which in itself may be dangerous. The root cause of diabetes may either be lack of insulin being produced by the pancreas or development of resistance towards insulin leading to no effect of insulin on the glucose level. Post-translational modifications of protein control various biological processes. It is also considered as an important process in the pathogenesis of diabetes mellitus.In the current review, we will discuss the recent developments in post translational modification of genes associated with diabetes as well as epigenetic modification and metabolic memory that maybe responsible for the onset of diabetes and its associated complications. Currently research is being conducted on high molecular weight adiponectin, peroxisome proliferator-activated receptors (PPARγ), epigenetic histone modifications and Calpain 10 (CAPN10 gene encoded) protein based upon the post translational modifications they undergo and how these modifications affect glucose level regulation. This review article aims at shedding light upon recent advances in biotechnology that are focussed on studying the nature of protein modifications that result in diabetes and finding ways to prevent these modifications or stimulate a new modification that may result in better control of the disease state if not a cure.
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Liu, Mengfeng, Xiran Yu, Shidong Xu, and Changfa Qu. "Establishing a Novel Gene Signature Related to Histone Modifications for Predicting Prognosis in Lung Adenocarcinoma." Journal of Oncology 2022 (September 23, 2022): 1–19. http://dx.doi.org/10.1155/2022/8802573.
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Background. Epigenetic modifications have been revealed to play an important role in tumorigenesis and tumor development. This study aims to analyze the role of histone modifications and the prognostic values of histone modifications in lung adenocarcinoma (LUAD). The promoters and enhancers of protein encoding genes (PCGs) were the regions of enriched histone modifications. Methods. Expression profiles and clinical information of LUAD samples were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Histone modification data of LUAD cell lines were downloaded from Encyclopedia of DNA Elements (ENCODE) database. Limma R package was used to identify differentially expressed PCGs. To identify molecular subtypes, consensus clustering was conducted based on the expression of dysregulated PCGs with abnormal histone modifications. Univariate Cox regression analysis and stepwise Akaike information criterion (stepAIC) were utilized to establish a prognostic model. Results. We identified a total of 699 epigenetic dysregulated genes with 122 of them significantly correlating with LUAD prognosis. We constructed three molecular subtypes (C1, C2, and C3) based on the 122 prognostic genes. C2 had the longest overall survival while C1 had the worst prognosis. In addition, three subtypes had differential immune infiltration and the response to immune checkpoint inhibitors. Moreover, we identified a risk model containing 5 epi-PCGs that had favorable performance to predict prognosis in different datasets. Conclusions. This study further supported the critical histone modifications in LUAD development. Three subtypes may provide guidance for the immunotherapy of LUAD patients. Importantly, the prognostic model had great potential to predict LUAD prognosis.
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Illam, Soorya P., Sruthi P. Kandiyil, and Achuthan C. Raghavamenon. "Targeting Histone Onco- Modifications Using Plant-Derived Products." Current Drug Targets 22, no. 11 (August 2, 2021): 1317–31. http://dx.doi.org/10.2174/1389450122666210118150716.
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The regulatory mechanisms lying over the genome that determines the differential expression of genes are termed epigenetic mechanisms. DNA methylation, acetylation, and phosphorylation of histone proteins and RNAi are typical examples. These epigenetic modifications are important determinants of normal growth and metabolism; at the same time, aberrant histone modifications play a major role in pathological conditions and are emerging as a new area of research for the last decades. Histone onco-modification is a term introduced by the scientific world to denote histone post-translational modifications that are associated with cancer development and progression. These modifications are likely to act in certain conditions as adaptive mechanisms to environmental and social factors. The enzymes that regulate DNA methylation as well as histone modifications are thus become a target for cancer therapy and chemoprevention. Since oxidative stress has been shown to modulate epigenetic changes, and phytocompounds with powerful antioxidant properties have a significant role in disease prevention. Nowadays, “nutri- epigenetics” is becoming an emerging area of research that deals with the influence of dietary compounds in epigenetics. This review aims to discuss the biological efficacy of promising phytocompounds that are able to counteract deleterious epigenetic modifications, especially histone onco- modifications.
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Hurtley, S. M. "Making Modifications." Science Signaling 3, no. 140 (September 21, 2010): ec290-ec290. http://dx.doi.org/10.1126/scisignal.3140ec290.
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Pauli, Cornelius, Michael Kienhöfer, Stefanie Göllner, and Carsten Müller-Tidow. "Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies." Biological Chemistry 402, no. 12 (October 11, 2021): 1531–46. http://dx.doi.org/10.1515/hsz-2021-0286.
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Abstract Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N 6-methyladenosine (m6A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2′-O-methylation (2′-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2′-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2′-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.
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Spöttel, Jenny, Johannes Brockelt, Sven Falke, and Sascha Rohn. "Characterization of Conjugates between α-Lactalbumin and Benzyl Isothiocyanate—Effects on Molecular Structure and Proteolytic Stability." Molecules 26, no. 20 (October 15, 2021): 6247. http://dx.doi.org/10.3390/molecules26206247.
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In complex foods, bioactive secondary plant metabolites (SPM) can bind to food proteins. Especially when being covalently bound, such modifications can alter the structure and, thus, the functional and biological properties of the proteins. Additionally, the bioactivity of the SPM can be affected as well. Consequently, knowledge of the influence of chemical modifications on these properties is particularly important for food processing, food safety, and nutritional physiology. As a model, the molecular structure of conjugates between the bioactive metabolite benzyl isothiocyanate (BITC, a hydrolysis product of the glucosinolate glucotropaeolin) and the whey protein α-lactalbumin (α-LA) was investigated using circular dichroism spectroscopy, anilino-1-naphthalenesulfonic acid fluorescence, and dynamic light scattering. Free amino groups were determined before and after the BITC conjugation. Finally, mass spectrometric analysis of the BITC-α-LA protein hydrolysates was performed. As a result of the chemical modifications, a change in the secondary structure of α-LA and an increase in surface hydrophobicity and hydrodynamic radii were documented. BITC modification at the ε-amino group of certain lysine side chains inhibited tryptic hydrolysis. Furthermore, two BITC-modified amino acids were identified, located at two lysine side chains (K32 and K113) in the amino acid sequence of α-LA.
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Brook, Matthew, Lora McCracken, James P. Reddington, Zhi-Liang Lu, Nicholas A. Morrice, and Nicola K. Gray. "The multifunctional poly(A)-binding protein (PABP) 1 is subject to extensive dynamic post-translational modification, which molecular modelling suggests plays an important role in co-ordinating its activities." Biochemical Journal 441, no. 3 (January 16, 2012): 803–16. http://dx.doi.org/10.1042/bj20111474.
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PABP1 [poly(A)-binding protein 1] is a central regulator of mRNA translation and stability and is required for miRNA (microRNA)-mediated regulation and nonsense-mediated decay. Numerous protein, as well as RNA, interactions underlie its multi-functional nature; however, it is unclear how its different activities are co-ordinated, since many partners interact via overlapping binding sites. In the present study, we show that human PABP1 is subject to elaborate post-translational modification, identifying 14 modifications located throughout the functional domains, all but one of which are conserved in mouse. Intriguingly, PABP1 contains glutamate and aspartate methylations, modifications of unknown function in eukaryotes, as well as lysine and arginine methylations, and lysine acetylations. The latter dramatically alter the pI of PABP1, an effect also observed during the cell cycle, suggesting that different biological processes/stimuli can regulate its modification status, although PABP1 also probably exists in differentially modified subpopulations within cells. Two lysine residues were differentially acetylated or methylated, revealing that PABP1 may be the first example of a cytoplasmic protein utilizing a ‘methylation/acetylation switch’. Modelling using available structures implicates these modifications in regulating interactions with individual PAM2 (PABP-interacting motif 2)-containing proteins, suggesting a direct link between PABP1 modification status and the formation of distinct mRNP (messenger ribonucleoprotein) complexes that regulate mRNA fate in the cytoplasm.
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Sachin, Palekar Gouri, Ashita S. Uppoor, and Sangeeta U. Nayak. "Nano-scale surface modification of dental implants – An emerging boon for osseointegration and biofilm control." Acta Marisiensis - Seria Medica 68, no. 4 (December 1, 2022): 154–58. http://dx.doi.org/10.2478/amma-2022-0029.
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Abstract Implant therapy is a commonly based method of replacing missing teeth. A range of physical, chemical, and biological modifications have been applied to the surface of titanium implants to improve their biological performance and osseointegration outcomes. Implant surface characteristics play an important function in several peri-implant cellular and molecular mechanisms. Clinicians are commonly placing dental implants with various surface roughness and modifications including plasma-sprayed, acid-etched, blasted, oxidized, hydroxyapatite-coated, or combinations of these procedures. Surface modifications are to facilitate early osseointegration and to ensure a long-term bone-to-implant contact without substantial marginal bone loss can be accomplished. It is apparent that different modifications have a range of beneficial effects, it is essential to consider at what time point and in what conditions these effects occur. This article reviews existing surface modification technologies of mainstream dental implants and the correlation between implant surface coatings and their performance of osseointegration or anti-bacterial ability it needs to be evaluated.
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Yu, Ningxi, Manasses Jora, Beulah Solivio, Priti Thakur, Carlos G. Acevedo-Rocha, Lennart Randau, Valérie de Crécy-Lagard, Balasubrahmanyam Addepalli, and Patrick A. Limbach. "tRNA Modification Profiles and Codon-Decoding Strategies in Methanocaldococcus jannaschii." Journal of Bacteriology 201, no. 9 (February 11, 2019). http://dx.doi.org/10.1128/jb.00690-18.
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ABSTRACT tRNAs play a critical role in mRNA decoding, and posttranscriptional modifications within tRNAs drive decoding efficiency and accuracy. The types and positions of tRNA modifications in model bacteria have been extensively studied, and tRNA modifications in a few eukaryotic organisms have also been characterized and localized to particular tRNA sequences. However, far less is known regarding tRNA modifications in archaea. While the identities of modifications have been determined for multiple archaeal organisms, Haloferax volcanii is the only organism for which modifications have been extensively localized to specific tRNA sequences. To improve our understanding of archaeal tRNA modification patterns and codon-decoding strategies, we have used liquid chromatography and tandem mass spectrometry to characterize and then map posttranscriptional modifications on 34 of the 35 unique tRNA sequences of Methanocaldococcus jannaschii. A new posttranscriptionally modified nucleoside, 5-cyanomethyl-2-thiouridine (cnm5s2U), was discovered and localized to position 34. Moreover, data consistent with wyosine pathway modifications were obtained beyond the canonical tRNAPhe as is typical for eukaryotes. The high-quality mapping of tRNA anticodon loops enriches our understanding of archaeal tRNA modification profiles and decoding strategies. IMPORTANCE While many posttranscriptional modifications in M. jannaschii tRNAs are also found in bacteria and eukaryotes, several that are unique to archaea were identified. By RNA modification mapping, the modification profiles of M. jannaschii tRNA anticodon loops were characterized, allowing a comparative analysis with H. volcanii modification profiles as well as a general comparison with bacterial and eukaryotic decoding strategies. This general comparison reveals that M. jannaschii, like H. volcanii, follows codon-decoding strategies similar to those used by bacteria, although position 37 appears to be modified to a greater extent than seen in H. volcanii.
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Chen, Hui-Ming, Hang Li, Meng-Xian Lin, Wei-Jie Fan, Yi Zhang, Yan-Ting Lin, and Shu-Xiang Wu. "Research Progress for RNA Modifications in Physiological and Pathological Angiogenesis." Frontiers in Genetics 13 (July 22, 2022). http://dx.doi.org/10.3389/fgene.2022.952667.
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As a critical layer of epigenetics, RNA modifications demonstrate various molecular functions and participate in numerous biological processes. RNA modifications have been shown to be essential for embryogenesis and stem cell fate. As high-throughput sequencing and antibody technologies advanced by leaps and bounds, the association of RNA modifications with multiple human diseases sparked research enthusiasm; in addition, aberrant RNA modification leads to tumor angiogenesis by regulating angiogenesis-related factors. This review collected recent cutting-edge studies focused on RNA modifications (N6-methyladenosine (m6A), N5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), and pseudopuridine (Ψ)), and their related regulators in tumor angiogenesis to emphasize the role and impact of RNA modifications.
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Biswas, Pritam, Aniruddha Adhikari, Uttam Pal, Susmita Mondal, Dipanjan Mukherjee, Ria Ghosh, Rami J. Obaid, et al. "A combined spectroscopic and molecular modeling Study on structure-function-dynamics under chemical modification: Alpha-chymotrypsin with formalin preservative." Frontiers in Chemistry 10 (August 31, 2022). http://dx.doi.org/10.3389/fchem.2022.978668.
Full textAbstract:
Enzyme function can be altered via modification of its amino acid residues, side chains and large-scale domain modifications. Herein, we have addressed the role of residue modification in catalytic activity and molecular recognition of an enzyme alpha-chymotrypsin (CHT) in presence of a covalent cross-linker formalin. Enzyme assay reveals reduced catalytic activity upon increased formalin concentration. Polarization gated anisotropy studies of a fluorophore 8-Anilino-1-naphthalenesulfonic acid (ANS) in CHT show a dip rise pattern in presence of formalin which is consistent with the generation of multiple ANS binding sites in the enzyme owing to modifications of its local amino acid residues. Molecular docking study on amino acid residue modifications in CHT also indicate towards the formation of multiple ANS binding site. The docking model also predicted no change in binding behavior for the substrate Ala-Ala-Phe-7-amido-4-methylcoumarin (AMC) at the active site upon formalin induced amino acid cross-linking.