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Biomolecules, Volume 7, Issue 1 (March 2017)

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Editorial

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Open AccessEditorial Acknowledgement to Reviewers of Biomolecules in 2016
Biomolecules 2017, 7(1), 4; doi:10.3390/biom7010004
Received: 12 January 2017 / Accepted: 12 January 2017 / Published: 12 January 2017
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Abstract The editors of Biomolecules would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.[...] Full article

Research

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Open AccessArticle Protection of the Queuosine Biosynthesis Enzyme QueF from Irreversible Oxidation by a Conserved Intramolecular Disulfide
Biomolecules 2017, 7(1), 30; doi:10.3390/biom7010030
Received: 10 January 2017 / Revised: 7 March 2017 / Accepted: 10 March 2017 / Published: 16 March 2017
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Abstract
QueF enzymes catalyze the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of the nitrile group of 7-cyano-7-deazaguanine (preQ0) to 7-aminomethyl-7-deazaguanine (preQ1) in the biosynthetic pathway to the tRNA modified nucleoside queuosine. The QueF-catalyzed reaction includes formation of a covalent thioimide
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QueF enzymes catalyze the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of the nitrile group of 7-cyano-7-deazaguanine (preQ0) to 7-aminomethyl-7-deazaguanine (preQ1) in the biosynthetic pathway to the tRNA modified nucleoside queuosine. The QueF-catalyzed reaction includes formation of a covalent thioimide intermediate with a conserved active site cysteine that is prone to oxidation in vivo. Here, we report the crystal structure of a mutant of Bacillus subtilis QueF, which reveals an unanticipated intramolecular disulfide formed between the catalytic Cys55 and a conserved Cys99 located near the active site. This structure is more symmetric than the substrate-bound structure and exhibits major rearrangement of the loops responsible for substrate binding. Mutation of Cys99 to Ala/Ser does not compromise enzyme activity, indicating that the disulfide does not play a catalytic role. Peroxide-induced inactivation of the wild-type enzyme is reversible with thioredoxin, while such inactivation of the Cys99Ala/Ser mutants is irreversible, consistent with protection of Cys55 from irreversible oxidation by disulfide formation with Cys99. Conservation of the cysteine pair, and the reported in vivo interaction of QueF with the thioredoxin-like hydroperoxide reductase AhpC in Escherichia coli suggest that regulation by the thioredoxin disulfide-thiol exchange system may constitute a general mechanism for protection of QueF from oxidative stress in vivo. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessArticle Role of Pseudouridine Formation by Deg1 for Functionality of Two Glutamine Isoacceptor tRNAs
Biomolecules 2017, 7(1), 8; doi:10.3390/biom7010008
Received: 16 December 2016 / Revised: 20 January 2017 / Accepted: 20 January 2017 / Published: 26 January 2017
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Abstract
Loss of Deg1/Pus3 and concomitant elimination of pseudouridine in tRNA at positions 38 and 39 (ψ38/39) was shown to specifically impair the function of tRNAGlnUUG under conditions of temperature-induced down-regulation of wobble uridine thiolation in budding yeast and is linked to
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Loss of Deg1/Pus3 and concomitant elimination of pseudouridine in tRNA at positions 38 and 39 (ψ38/39) was shown to specifically impair the function of tRNAGlnUUG under conditions of temperature-induced down-regulation of wobble uridine thiolation in budding yeast and is linked to intellectual disability in humans. To further characterize the differential importance of the frequent ψ38/39 modification for tRNAs in yeast, we analyzed the in vivo function of non-sense suppressor tRNAs SUP4 and sup70-65 in the absence of the modifier. In the tRNATyrGψA variant SUP4, UAA read-through is enabled due to an anticodon mutation (UψA), whereas sup70-65 is a mutant form of tRNAGlnCUG (SUP70) that mediates UAG decoding due to a mutation of the anticodon-loop closing base pair (G31:C39 to A31:C39). While SUP4 function is unaltered in deg1/pus3 mutants, the ability of sup70-65 to mediate non-sense suppression and to complement a genomic deletion of the essential SUP70 gene is severely compromised. These results and the differential suppression of growth defects in deg1 mutants by multi-copy SUP70 or tQ(UUG) are consistent with the interpretation that ψ38 is most important for tRNAGlnUUG function under heat stress but becomes crucial for tRNAGlnCUG as well when the anticodon loop is destabilized by the sup70-65 mutation. Thus, ψ38/39 may protect the anticodon loop configuration from disturbances by loss of other modifications or base changes. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessArticle A Novel Diterpene Glycoside with Nine Glucose Units from Stevia rebaudiana Bertoni
Biomolecules 2017, 7(1), 10; doi:10.3390/biom7010010
Received: 18 November 2016 / Accepted: 23 January 2017 / Published: 31 January 2017
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Abstract
Following our interest in new diterpene glycosides with better taste profiles than that of Rebaudioside M, we have recently isolated and characterized Rebaudioside IX—a novel steviol glycoside—from a commercially‐supplied extract of Stevia rebaudiana Bertoni. This molecule contains a hexasaccharide group attached at C‐13
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Following our interest in new diterpene glycosides with better taste profiles than that of Rebaudioside M, we have recently isolated and characterized Rebaudioside IX—a novel steviol glycoside—from a commercially‐supplied extract of Stevia rebaudiana Bertoni. This molecule contains a hexasaccharide group attached at C‐13 of the central diterpene core, and contains three additional glucose units when compared with Rebaudioside M. Here we report the complete structure elucidation—based on extensive Nuclear Magnetic Resonance (NMR) analysis (1H, 13C, Correlation Spectroscopy (COSY), Heteronuclear Single Quantum Coherence‐Distortionless Enhancement Polarization Transfer (HSQC‐DEPT), Heteronuclear Multiple Bond Correlation (HMBC), 1D Total Correlation Spectroscopy (TOCSY), Nuclear Overhauser Effect Spectroscopy (NOESY)) and mass spectral data—of this novel diterpene glycoside with nine sugar moieties and containing a relatively rare 16 α‐linked glycoside. A steviol glycoside bearing nine glucose units is unprecedented in the literature, and could have an impact on the natural sweetener catalog. Full article
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Open AccessArticle Differential Degradation and Detoxification of an Aromatic Pollutant by Two Different Peroxidases
Biomolecules 2017, 7(1), 31; doi:10.3390/biom7010031
Received: 14 February 2017 / Revised: 4 March 2017 / Accepted: 13 March 2017 / Published: 18 March 2017
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Abstract
Enzymatic degradation of organic pollutants is a new and promising remediation approach. Peroxidases are one of the most commonly used classes of enzymes to degrade organic pollutants. However, it is generally assumed that all peroxidases behave similarly and produce similar degradation products. In
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Enzymatic degradation of organic pollutants is a new and promising remediation approach. Peroxidases are one of the most commonly used classes of enzymes to degrade organic pollutants. However, it is generally assumed that all peroxidases behave similarly and produce similar degradation products. In this study, we conducted detailed studies of the degradation of a model aromatic pollutant, Sulforhodamine B dye (SRB dye), using two peroxidases—soybean peroxidase (SBP) and chloroperoxidase (CPO). Our results show that these two related enzymes had different optimum conditions (pH, temperature, H2O2 concentration, etc.) for efficiently degrading SRB dye. High-performance liquid chromatography and liquid chromatography –mass spectrometry analyses confirmed that both SBP and CPO transformed the SRB dye into low molecular weight intermediates. While most of the intermediates produced by the two enzymes were the same, the CPO treatment produced at least one different intermediate. Furthermore, toxicological evaluation using lettuce (Lactuca sativa) seeds demonstrated that the SBP-based treatment was able to eliminate the phytotoxicity of SRB dye, but the CPO-based treatment did not. Our results show, for the first time, that while both of these related enzymes can be used to efficiently degrade organic pollutants, they have different optimum reaction conditions and may not be equally efficient in detoxification of organic pollutants. Full article
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Open AccessArticle The Escherichia coli COG1738 Member YhhQ Is Involved in 7-Cyanodeazaguanine (preQ0) Transport
Biomolecules 2017, 7(1), 12; doi:10.3390/biom7010012
Received: 22 December 2016 / Revised: 27 January 2017 / Accepted: 30 January 2017 / Published: 8 February 2017
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Abstract
Queuosine (Q) is a complex modification of the wobble base in tRNAs with GUN anticodons. The full Q biosynthesis pathway has been elucidated in Escherichia coli. FolE, QueD, QueE and QueC are involved in the conversion of guanosine triphosphate (GTP) to 7-cyano-7-deazaguanine
[...] Read more.
Queuosine (Q) is a complex modification of the wobble base in tRNAs with GUN anticodons. The full Q biosynthesis pathway has been elucidated in Escherichia coli. FolE, QueD, QueE and QueC are involved in the conversion of guanosine triphosphate (GTP) to 7-cyano-7-deazaguanine (preQ0), an intermediate of increasing interest for its central role in tRNA and DNA modification and secondary metabolism. QueF then reduces preQ0 to 7-aminomethyl-7-deazaguanine (preQ1). PreQ1 is inserted into tRNAs by tRNA guanine(34) transglycosylase (TGT). The inserted base preQ1 is finally matured to Q by two additional steps involving QueA and QueG or QueH. Most Eubacteria harbor the full set of Q synthesis genes and are predicted to synthesize Q de novo. However, some bacteria only encode enzymes involved in the second half of the pathway downstream of preQ0 synthesis, including the signature enzyme TGT. Different patterns of distribution of the queF, tgt, queA and queG or queH genes are observed, suggesting preQ0, preQ1 or even the queuine base being salvaged in specific organisms. Such salvage pathways require the existence of specific 7-deazapurine transporters that have yet to be identified. The COG1738 family was identified as a candidate for a missing preQ0/preQ1 transporter in prokaryotes, by comparative genomics analyses. The existence of Q precursor salvage was confirmed for the first time in bacteria, in vivo, through an indirect assay. The involvement of the COG1738 in salvage of a Q precursor was experimentally validated in Escherichia coli, where it was shown that the COG1738 family member YhhQ is essential for preQ0 transport. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessArticle Next‐Generation Sequencing‐Based RiboMethSeq Protocol for Analysis of tRNA 2′‐O‐Methylation
Biomolecules 2017, 7(1), 13; doi:10.3390/biom7010013
Received: 29 December 2016 / Accepted: 2 February 2017 / Published: 9 February 2017
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Abstract
Analysis of RNA modifications by traditional physico‐chemical approaches is labor intensive, requires substantial amounts of input material and only allows site‐by‐site measurements. The recent development of qualitative and quantitative approaches based on next‐generation sequencing (NGS) opens new perspectives for the analysis of various
[...] Read more.
Analysis of RNA modifications by traditional physico‐chemical approaches is labor intensive, requires substantial amounts of input material and only allows site‐by‐site measurements. The recent development of qualitative and quantitative approaches based on next‐generation sequencing (NGS) opens new perspectives for the analysis of various cellular RNA species. The Illumina sequencing‐based RiboMethSeq protocol was initially developed and successfully applied for mapping of ribosomal RNA (rRNA) 2′‐O‐methylations. This method also gives excellent results in the quantitative analysis of rRNA modifications in different species and under varying growth conditions. However, until now, RiboMethSeq was only employed for rRNA, and the whole sequencing and analysis pipeline was only adapted to this long and rather conserved RNA species. A deep understanding of RNA modification functions requires large and global analysis datasets for other important RNA species, namely for transfer RNAs (tRNAs), which are well known to contain a great variety of functionally‐important modified residues. Here, we evaluated the application of the RiboMethSeq protocol for the analysis of tRNA 2′‐O‐methylation in Escherichia coli and in Saccharomyces cerevisiae. After a careful optimization of the bioinformatic pipeline, RiboMethSeq proved to be suitable for relative quantification of methylation rates for known modified positions in different tRNA species. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessArticle Modulation of the Proteostasis Machinery to  Overcome Stress Caused by Diminished Levels of  t6A‐Modified tRNAs in Drosophila
Biomolecules 2017, 7(1), 25; doi:10.3390/biom7010025
Received: 30 November 2016 / Accepted: 28 February 2017 / Published: 6 March 2017
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Abstract
Transfer RNAs (tRNAs) harbor a subset of post‐transcriptional modifications required for structural stability or decoding function. N6‐threonylcarbamoyladenosine (t6A) is a universally conserved modification found at position 37 in tRNA that pair A‐starting codons (ANN) and is required for proper translation initiation and to
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Transfer RNAs (tRNAs) harbor a subset of post‐transcriptional modifications required for structural stability or decoding function. N6‐threonylcarbamoyladenosine (t6A) is a universally conserved modification found at position 37 in tRNA that pair A‐starting codons (ANN) and is required for proper translation initiation and to prevent frame shift during elongation. In its absence, the synthesis of aberrant proteins is likely, evidenced by the formation of protein aggregates. In this work, our aim was to study the relationship between t6A‐modified tRNAs and protein synthesis homeostasis machinery using Drosophila melanogaster. We used the Gal4/UAS system to knockdown genes required for t6A synthesis in a tissue and time specific manner and in vivo reporters of unfolded protein response (UPR) activation. Our results suggest that t6A‐modified tRNAs, synthetized by the threonyl‐carbamoyl transferase complex (TCTC), are required for organismal growth and imaginal cell survival, and is most likely to support proper protein synthesis. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessArticle Effect of Reduction of Redox Modifications of Cys-Residues in the Na,K-ATPase α1-Subunit on Its Activity
Biomolecules 2017, 7(1), 18; doi:10.3390/biom7010018
Received: 16 November 2016 / Revised: 3 February 2017 / Accepted: 6 February 2017 / Published: 21 February 2017
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Abstract
Sodium-potassium adenosine triphosphatase (Na,K-ATPase) creates a gradient of sodium and potassium ions necessary for the viability of animal cells, and it is extremely sensitive to intracellular redox status. Earlier we found that regulatory glutathionylation determines Na,K-ATPase redox sensitivity but the role of basal
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Sodium-potassium adenosine triphosphatase (Na,K-ATPase) creates a gradient of sodium and potassium ions necessary for the viability of animal cells, and it is extremely sensitive to intracellular redox status. Earlier we found that regulatory glutathionylation determines Na,K-ATPase redox sensitivity but the role of basal glutathionylation and other redox modifications of cysteine residues is not clear. The purpose of this study was to detect oxidized, nitrosylated, or glutathionylated cysteine residues in Na,K-ATPase, evaluate the possibility of removing these modifications and assess their influence on the enzyme activity. To this aim, we have detected such modifications in the Na,K-ATPase α1-subunit purified from duck salt glands and tried to eliminate them by chemical reducing agents and the glutaredoxin1/glutathione reductase enzyme system. Detection of cysteine modifications was performed using mass spectrometry and Western blot analysis. We have found that purified Na,K-ATPase α1-subunit contains glutathionylated, nitrosylated, and oxidized cysteines. Chemical reducing agents partially eliminate these modifications that leads to the slight increase of the enzyme activity. Enzyme system glutaredoxin/glutathione reductase, unlike chemical reducing agents, produces significant increase of the enzyme activity. At the same time, the enzyme system deglutathionylates native Na,K-ATPase to a lesser degree than chemical reducing agents. This suggests that the enzymatic reducing system glutaredoxin/glutathione reductase specifically affects glutathionylation of the regulatory cysteine residues of Na,K-ATPase α1-subunit. Full article
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Open AccessArticle Evaluation of Stability of Amylose Inclusion Complexes Depending on Guest Polymers and Their Application to Supramolecular Polymeric Materials
Biomolecules 2017, 7(1), 28; doi:10.3390/biom7010028
Received: 20 February 2017 / Revised: 9 March 2017 / Accepted: 9 March 2017 / Published: 15 March 2017
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Abstract
This paper describes the evaluation of the stability of amylose–polymer inclusion complexes under solution state in dimethyl sulfoxide (DMSO) depending on guest polymers. The three complexes were prepared by the vine-twining polymerization method using polytetrahydrofuran (PTHF), poly(ε-caprolactone) (PCL), and poly(l-lactide) (PLLA)
[...] Read more.
This paper describes the evaluation of the stability of amylose–polymer inclusion complexes under solution state in dimethyl sulfoxide (DMSO) depending on guest polymers. The three complexes were prepared by the vine-twining polymerization method using polytetrahydrofuran (PTHF), poly(ε-caprolactone) (PCL), and poly(l-lactide) (PLLA) as guest polymers. The stability investigation was conducted at desired temperatures (25, 30, 40, 60 °C) in DMSO solutions of the complexes. Consequently, the amylose–PTHF inclusion complex was dissociated at 25 °C, while the other complexes were stable under the same conditions. When the temperatures were elevated, the amylose–PCL and amylose–PLLA complexes were dissociated at 40 and 60 °C, respectively. We also found that amylose inclusion supramolecular polymers which were prepared by the vine-twining polymerization using primer-guest conjugates formed films by the acetylation of amylose segments. The film from acetylated amylose–PLLA supramolecular polymer had higher storage modulus than that from acetylated amylose–PTHF supramolecular polymer, as a function of temperature. Full article
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Review

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Open AccessFeature PaperReview Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis
Biomolecules 2017, 7(1), 1; doi:10.3390/biom7010001
Received: 31 October 2016 / Revised: 12 December 2016 / Accepted: 14 December 2016 / Published: 27 December 2016
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Abstract
Precise duplication of the genome is a prerequisite for the health and longevity of multicellular organisms. The temporal regulation of origin specification, replication licensing, and firing at replication origins is mediated by the cyclin-dependent kinases. Here the role of Cip1 interacting Zinc finger
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Precise duplication of the genome is a prerequisite for the health and longevity of multicellular organisms. The temporal regulation of origin specification, replication licensing, and firing at replication origins is mediated by the cyclin-dependent kinases. Here the role of Cip1 interacting Zinc finger protein 1 (Ciz1) in regulation of cell cycle progression is discussed. Ciz1 contributes to regulation of the G1/S transition in mammalian cells. Ciz1 contacts the pre-replication complex (pre-RC) through cell division cycle 6 (Cdc6) interactions and aids localization of cyclin A- cyclin-dependent kinase 2 (CDK2) activity to chromatin and the nuclear matrix during initiation of DNA replication. We discuss evidence that Ciz1 serves as a kinase sensor that regulates both initiation of DNA replication and prevention of re-replication. Finally, the emerging role for Ciz1 in cancer biology is discussed. Ciz1 is overexpressed in common tumors and tumor growth is dependent on Ciz1 expression, suggesting that Ciz1 is a driver of tumor growth. We present evidence that Ciz1 may contribute to deregulation of the cell cycle due to its ability to alter the CDK activity thresholds that are permissive for initiation of DNA replication. We propose that Ciz1 may contribute to oncogenesis by induction of DNA replication stress and that Ciz1 may be a multifaceted target in cancer therapy. Full article
(This article belongs to the Special Issue Chromosome Maintenance)
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Open AccessReview Critical Minireview: The Fate of tRNACys during Oxidative Stress in Bacillus subtilis
Biomolecules 2017, 7(1), 6; doi:10.3390/biom7010006
Received: 14 November 2016 / Revised: 12 January 2017 / Accepted: 13 January 2017 / Published: 20 January 2017
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Abstract
Oxidative stress occurs when cells are exposed to elevated levels of reactive oxygen species that can damage biological molecules. One bacterial response to oxidative stress involves disulfide bond formation either between protein thiols or between protein thiols and low-molecular-weight (LMW) thiols. Bacillithiol was
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Oxidative stress occurs when cells are exposed to elevated levels of reactive oxygen species that can damage biological molecules. One bacterial response to oxidative stress involves disulfide bond formation either between protein thiols or between protein thiols and low-molecular-weight (LMW) thiols. Bacillithiol was recently identified as a major low-molecular-weight thiol in Bacillus subtilis and related Firmicutes. Four genes (bshA, bshB1, bshB2, and bshC) are involved in bacillithiol biosynthesis. The bshA and bshB1 genes are part of a seven-gene operon (ypjD), which includes the essential gene cca, encoding CCA-tRNA nucleotidyltransferase. The inclusion of cca in the operon containing bacillithiol biosynthetic genes suggests that the integrity of the 3′ terminus of tRNAs may also be important in oxidative stress. The addition of the 3′ terminal CCA sequence by CCA-tRNA nucleotidyltransferase to give rise to a mature tRNA and functional molecules ready for aminoacylation plays an essential role during translation and expression of the genetic code. Any defects in these processes, such as the accumulation of shorter and defective tRNAs under oxidative stress, might exert a deleterious effect on cells. This review summarizes the physiological link between tRNACys regulation and oxidative stress in Bacillus. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes
Biomolecules 2017, 7(1), 5; doi:10.3390/biom7010005
Received: 8 December 2016 / Revised: 4 January 2017 / Accepted: 9 January 2017 / Published: 14 January 2017
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Abstract
Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the
[...] Read more.
Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the thiomodifications xm5s2U at the wobble position 34 in tRNAs for Lys, Gln and Glu, were suggested to have an important role during the translation process by ensuring accurate deciphering of the genetic code and by stabilization of the tRNA structure. The trafficking and delivery of sulfur nucleosides is a complex process carried out by sulfur relay systems involving numerous proteins, which not only deliver sulfur to the specific tRNAs but also to other sulfur-containing molecules including iron–sulfur clusters, thiamin, biotin, lipoic acid and molybdopterin (MPT). Among the biosynthesis of these sulfur-containing molecules, the biosynthesis of the molybdenum cofactor (Moco) and the synthesis of thio-modified tRNAs in particular show a surprising link by sharing protein components for sulfur mobilization in pro- and eukaryotes. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?
Biomolecules 2017, 7(1), 2; doi:10.3390/biom7010002
Received: 16 November 2016 / Revised: 20 December 2016 / Accepted: 26 December 2016 / Published: 4 January 2017
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Abstract
Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as “blood substitutes”. Human trials conducted so far by several manufactures in a variety of clinical indications, including
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Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as “blood substitutes”. Human trials conducted so far by several manufactures in a variety of clinical indications, including trauma, and elective surgeries have failed and no product has gained the Food and Drug Administration approval for human use. Safety concerns due to frequent incidences of hemodynamic, cardiac events, and even death led to the termination of some of these trials. Several second generation HBOC products that have been chemically and/or genetically modified (or in some cases ligated with carbon monoxide (CO)) found a new clinical application in conditions as complex as sickle cell disease (SCD). By virtue of higher oxygen affinity (P50) (R-state), and smaller size, HBOCs may be able to reach the microvasculature unload of oxygen to reverse the cycles of sickling/unsickling of the deoxy-sickle cell Hb (HbS) (T-state), thus preventing vaso-occlusion, a central event in SCD pathophysiology. However, biochemically, it is thought that outside the red blood cell (due to frequent hemolysis), free HbS or infused HBOCs are capable of interfering with a number of oxidative and signaling pathways and may, thus, negate any benefit that HBOCs may provide. This review discusses the advantages and disadvantages of using HBOCs in SCD. Full article
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Open AccessReview Trm112, a Protein Activator of Methyltransferases Modifying Actors of the Eukaryotic Translational Apparatus
Biomolecules 2017, 7(1), 7; doi:10.3390/biom7010007
Received: 13 December 2016 / Revised: 16 January 2017 / Accepted: 18 January 2017 / Published: 27 January 2017
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Abstract
Post-transcriptional and post-translational modifications are very important for the control and optimal efficiency of messenger RNA (mRNA) translation. Among these, methylation is the most widespread modification, as it is found in all domains of life. These methyl groups can be grafted either on
[...] Read more.
Post-transcriptional and post-translational modifications are very important for the control and optimal efficiency of messenger RNA (mRNA) translation. Among these, methylation is the most widespread modification, as it is found in all domains of life. These methyl groups can be grafted either on nucleic acids (transfer RNA (tRNA), ribosomal RNA (rRNA), mRNA, etc.) or on protein translation factors. This review focuses on Trm112, a small protein interacting with and activating at least four different eukaryotic methyltransferase (MTase) enzymes modifying factors involved in translation. The Trm112-Trm9 and Trm112-Trm11 complexes modify tRNAs, while the Trm112-Mtq2 complex targets translation termination factor eRF1, which is a tRNA mimic. The last complex formed between Trm112 and Bud23 proteins modifies 18S rRNA and participates in the 40S biogenesis pathway. In this review, we present the functions of these eukaryotic Trm112-MTase complexes, the molecular bases responsible for complex formation and substrate recognition, as well as their implications in human diseases. Moreover, as Trm112 orthologs are found in bacterial and archaeal genomes, the conservation of this Trm112 network beyond eukaryotic organisms is also discussed. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Key Events Participating in the Pathogenesis of Alcoholic Liver Disease
Biomolecules 2017, 7(1), 9; doi:10.3390/biom7010009
Received: 21 December 2016 / Accepted: 20 January 2017 / Published: 27 January 2017
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Abstract
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress
[...] Read more.
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currentlyonly partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aimsto introduce the reader to the concept of alcohol‐mediated liver damage and the mechanisms driving injury. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessReview DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge
Biomolecules 2017, 7(1), 3; doi:10.3390/biom7010003
Received: 15 November 2016 / Revised: 8 December 2016 / Accepted: 12 December 2016 / Published: 5 January 2017
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Abstract
Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each
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Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview m1A Post‐Transcriptional Modification in tRNAs
Biomolecules 2017, 7(1), 20; doi:10.3390/biom7010020
Received: 16 January 2017 / Accepted: 16 February 2017 / Published: 21 February 2017
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Abstract
To date, about 90 post‐transcriptional modifications have been reported in tRNA expanding their chemical and functional diversity. Methylation is the most frequent post‐transcriptional tRNA modification that can occur on almost all nitrogen sites of the nucleobases, on the C5 atom of pyrimidines, on
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To date, about 90 post‐transcriptional modifications have been reported in tRNA expanding their chemical and functional diversity. Methylation is the most frequent post‐transcriptional tRNA modification that can occur on almost all nitrogen sites of the nucleobases, on the C5 atom of pyrimidines, on the C2 and C8 atoms of adenosine and, additionally, on the oxygen of the ribose 2′-OH. The methylation on the N1 atom of adenosine to form 1‐methyladenosine (m1A) has been identified at nucleotide position 9, 14, 22, 57, and 58 in different tRNAs. In some cases, these modifications have been shown to increase tRNA structural stability and induce correct tRNA folding. This review provides an overview of the currently known m1A modifications, the different m1A modification sites, the biological role of each modification, and the enzyme responsible for each methylation in different species. The review further describes, in detail, two enzyme families responsible for formation of m1A at nucleotide position 9 and 58 in tRNA with a focus on the tRNA binding, m1A mechanism, protein domain organisation and overall structures. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis
Biomolecules 2017, 7(1), 11; doi:10.3390/biom7010011
Received: 7 November 2016 / Revised: 26 January 2017 / Accepted: 30 January 2017 / Published: 8 February 2017
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Abstract
The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory–Denk body (MDB)
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The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory–Denk body (MDB) formation develops in the hepatocytes in alcoholic hepatitis as a consequence of the failure of these protein quality control mechanisms to remove misfolded and damaged proteins and to prevent MDB aggresome formation within the cytoplasm of hepatocytes. The proteins involved in the quality control pathways are identified, quantitated, and visualized by immunofluorescent antibody staining of liver biopsies from patients with AH. Quantification of the proteins are achieved by measuring the fluorescent intensity using a morphometric system. Ufmylation and FAT10ylation pathways were downregulated, Mca1 pathways were upregulated, autophagocytosis was upregulated, and ER stress PERK (protein kinase RNA-like endoplasmic reticulum kinase) and CHOP (CCAAT/enhancer-binding protein homologous protein) mechanisms were upregulated. In conclusion: Despite the upregulation of several pathways of protein quality control, aggresomes (MDBs) still formed in the hepatocytes in AH. The pathogenesis of AH is due to the failure of protein quality control, which causes balloon-cell change with MDB formation and ER stress. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessReview Mapping Post‐Transcriptional Modifications onto Transfer Ribonucleic Acid Sequences by Liquid Chromatography Tandem Mass Spectrometry
Biomolecules 2017, 7(1), 21; doi:10.3390/biom7010021
Received: 30 December 2016 / Accepted: 15 February 2017 / Published: 22 February 2017
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Abstract
Liquid chromatography, coupled with tandem mass spectrometry, has become one of the most popular methods for the analysis of post‐transcriptionally modified transfer ribonucleic acids (tRNAs). Given that the information collected using this platform is entirely determined by the mass of the analyte, it
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Liquid chromatography, coupled with tandem mass spectrometry, has become one of the most popular methods for the analysis of post‐transcriptionally modified transfer ribonucleic acids (tRNAs). Given that the information collected using this platform is entirely determined by the mass of the analyte, it has proven to be the gold standard for accurately assigning nucleobases to the sequence. For the past few decades many labs have worked to improve the analysis, contiguous to instrumentation manufacturers developing faster and more sensitive instruments. With biological discoveries relating to ribonucleic acid happening more frequently, mass spectrometry has been invaluable in helping to understand what is happening at the molecular level. Here we present a brief overview of the methods that have been developed and refined for the analysis of modified tRNAs by liquid chromatography tandem mass spectrometry. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Trm5 and TrmD: Two Enzymes from Distinct Origins Catalyze the Identical tRNA Modification, m1G37
Biomolecules 2017, 7(1), 32; doi:10.3390/biom7010032
Received: 13 February 2017 / Revised: 7 March 2017 / Accepted: 16 March 2017 / Published: 21 March 2017
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Abstract
The N1-atom of guanosine at position 37 in transfer RNA (tRNA) is methylated by tRNA methyltransferase 5 (Trm5) in eukaryotes and archaea, and by tRNA methyltransferase D (TrmD) in bacteria. The resultant modified nucleotide m1G37 positively regulates the aminoacylation
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The N1-atom of guanosine at position 37 in transfer RNA (tRNA) is methylated by tRNA methyltransferase 5 (Trm5) in eukaryotes and archaea, and by tRNA methyltransferase D (TrmD) in bacteria. The resultant modified nucleotide m1G37 positively regulates the aminoacylation of the tRNA, and simultaneously functions to prevent the +1 frameshift on the ribosome. Interestingly, Trm5 and TrmD have completely distinct origins, and therefore bear different tertiary folds. In this review, we describe the different strategies utilized by Trm5 and TrmD to recognize their substrate tRNAs, mainly based on their crystal structures complexed with substrate tRNAs. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury
Biomolecules 2017, 7(1), 22; doi:10.3390/biom7010022
Received: 16 January 2017 / Revised: 15 February 2017 / Accepted: 20 February 2017 / Published: 2 March 2017
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Abstract
Divalent metal ions are essential nutrients for all living organisms and are commonly protein-bound where they perform important roles in protein structure and function. This regulatory control from metals is observed in the relatively abundant plasma protein histidine-rich glycoprotein (HRG), which displays preferential
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Divalent metal ions are essential nutrients for all living organisms and are commonly protein-bound where they perform important roles in protein structure and function. This regulatory control from metals is observed in the relatively abundant plasma protein histidine-rich glycoprotein (HRG), which displays preferential binding to the second most abundant transition element in human systems, Zinc (Zn2+). HRG has been proposed to interact with a large number of protein ligands and has been implicated in the regulation of various physiological and pathological processes including the formation of immune complexes, apoptotic/necrotic and pathogen clearance, cell adhesion, antimicrobial activity, angiogenesis, coagulation and fibrinolysis. Interestingly, these processes are often associated with sites of tissue injury or tumour growth, where the concentration and distribution of Zn2+ is known to vary. Changes in Zn2+ levels have been shown to modify HRG function by altering its affinity for certain ligands and/or providing protection against proteolytic disassembly by serine proteases. This review focuses on the molecular interplay between HRG and Zn2+, and how Zn2+ binding modifies HRG-ligand interactions to regulate function in different settings of tissue injury. Full article
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Open AccessReview Diverse Mechanisms of Sulfur Decoration in Bacterial tRNA and Their Cellular Functions
Biomolecules 2017, 7(1), 33; doi:10.3390/biom7010033
Received: 6 February 2017 / Revised: 10 March 2017 / Accepted: 16 March 2017 / Published: 22 March 2017
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Abstract
Sulfur-containing transfer ribonucleic acids (tRNAs) are ubiquitous biomolecules found in all organisms that possess a variety of functions. For decades, their roles in processes such as translation, structural stability, and cellular protection have been elucidated and appreciated. These thionucleosides are found in all
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Sulfur-containing transfer ribonucleic acids (tRNAs) are ubiquitous biomolecules found in all organisms that possess a variety of functions. For decades, their roles in processes such as translation, structural stability, and cellular protection have been elucidated and appreciated. These thionucleosides are found in all types of bacteria; however, their biosynthetic pathways are distinct among different groups of bacteria. Considering that many of the thio-tRNA biosynthetic enzymes are absent in Gram-positive bacteria, recent studies have addressed how sulfur trafficking is regulated in these prokaryotic species. Interestingly, a novel proposal has been given for interplay among thionucleosides and the biosynthesis of other thiocofactors, through participation of shared-enzyme intermediates, the functions of which are impacted by the availability of substrate as well as metabolic demand of thiocofactors. This review describes the occurrence of thio-modifications in bacterial tRNA and current methods for detection of these modifications that have enabled studies on the biosynthesis and functions of S-containing tRNA across bacteria. It provides insight into potential modes of regulation and potential evolutionary events responsible for divergence in sulfur metabolism among prokaryotes. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Transfer RNA methyltransferases with a SpoU‐TrmD  (SPOUT) fold and their modified nucleosides in  tRNA
Biomolecules 2017, 7(1), 23; doi:10.3390/biom7010023
Received: 7 January 2017 / Accepted: 23 February 2017 / Published: 28 February 2017
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Abstract
The existence of SpoU‐TrmD (SPOUT) RNA methyltransferase superfamily was first predicted by bioinformatics. SpoU is the previous name of TrmH, which catalyzes the 2’‐Omethylation of ribose of G18 in tRNA; TrmD catalyzes the formation of N1‐methylguanosine at position 37 in tRNA. Although SpoU
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The existence of SpoU‐TrmD (SPOUT) RNA methyltransferase superfamily was first predicted by bioinformatics. SpoU is the previous name of TrmH, which catalyzes the 2’‐Omethylation of ribose of G18 in tRNA; TrmD catalyzes the formation of N1‐methylguanosine at position 37 in tRNA. Although SpoU (TrmH) and TrmD were originally considered to be unrelated, the bioinformatics study suggested that they might share a common evolution origin and form a single superfamily. The common feature of SPOUT RNA methyltransferases is the formation of a deep trefoil knot in the catalytic domain. In the past decade, the SPOUT RNA methyltransferase superfamily has grown; furthermore, knowledge concerning the functions of their modified nucleosides in tRNA has also increased. Some enzymes are potential targets in the design of antibacterial drugs. In humans, defects in some genes may be related to carcinogenesis. In this review, recent findings on the tRNA methyltransferases with a SPOUT fold and their methylated nucleosides in tRNA, including classification of tRNA methyltransferases with a SPOUT fold; knot structures, domain arrangements, subunit structures and reaction mechanisms; tRNA recognition mechanisms, and functions of modified nucleosides synthesized by this superfamily, are summarized. Lastly, the future perspective for studies on tRNA modification enzymes are considered. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Dealing with an Unconventional Genetic Code in  Mitochondria: The Biogenesis and Pathogenic  Defects of the 5‐Formylcytosine Modification in  Mitochondrial tRNAMet
Biomolecules 2017, 7(1), 24; doi:10.3390/biom7010024
Received: 13 January 2017 / Accepted: 24 February 2017 / Published: 2 March 2017
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Abstract
Human mitochondria contain their own genome, which uses an unconventional genetic code. In addition to the standard AUG methionine codon, the single mitochondrial tRNA Methionine (mt‐tRNAMet) also recognises AUA during translation initiation and elongation. Post‐transcriptional modifications of tRNAs are important for structure, stability,
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Human mitochondria contain their own genome, which uses an unconventional genetic code. In addition to the standard AUG methionine codon, the single mitochondrial tRNA Methionine (mt‐tRNAMet) also recognises AUA during translation initiation and elongation. Post‐transcriptional modifications of tRNAs are important for structure, stability, correct folding and aminoacylation as well as decoding. The unique 5‐formylcytosine (f5C) modification of position 34 in mt‐tRNAMet has been long postulated to be crucial for decoding of unconventional methionine codons and efficient mitochondrial translation. However, the enzymes responsible for the formation of mitochondrial f5C have been identified only recently. The first step of the f5C pathway consists of methylation of cytosine by NSUN3. This is followed by further oxidation by ABH1. Here, we review the role of f5C, the latest breakthroughs in our understanding of the biogenesis of this unique mitochondrial tRNA modification and its involvement in human disease. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification
Biomolecules 2017, 7(1), 14; doi:10.3390/biom7010014
Received: 19 December 2016 / Revised: 2 February 2017 / Accepted: 2 February 2017 / Published: 10 February 2017
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Abstract
Enzymes of the Dnmt2 family of methyltransferases have yielded a number of unexpected discoveries. The first surprise came more than ten years ago when it was realized that, rather than being DNA methyltransferases, Dnmt2 enzymes actually are transfer RNA (tRNA) methyltransferases for cytosine-5
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Enzymes of the Dnmt2 family of methyltransferases have yielded a number of unexpected discoveries. The first surprise came more than ten years ago when it was realized that, rather than being DNA methyltransferases, Dnmt2 enzymes actually are transfer RNA (tRNA) methyltransferases for cytosine-5 methylation, foremost C38 (m5C38) of tRNAAsp. The second unanticipated finding was our recent discovery of a nutritional regulation of Dnmt2 in the fission yeast Schizosaccharomyces pombe. Significantly, the presence of the nucleotide queuosine in tRNAAsp strongly stimulates Dnmt2 activity both in vivo and in vitro in S. pombe. Queuine, the respective base, is a hypermodified guanine analog that is synthesized from guanosine-5’-triphosphate (GTP) by bacteria. Interestingly, most eukaryotes have queuosine in their tRNA. However, they cannot synthesize it themselves, but rather salvage it from food or from gut microbes. The queuine obtained from these sources comes from the breakdown of tRNAs, where the queuine ultimately was synthesized by bacteria. Queuine thus has been termed a micronutrient. This review summarizes the current knowledge of Dnmt2 methylation and queuosine modification with respect to translation as well as the organismal consequences of the absence of these modifications. Models for the functional cooperation between these modifications and its wider implications are discussed. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer
Biomolecules 2017, 7(1), 15; doi:10.3390/biom7010015
Received: 30 November 2016 / Revised: 23 January 2017 / Accepted: 6 February 2017 / Published: 14 February 2017
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Abstract
The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental
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The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental and homeostasis processes, as well as being a cancer-driver mechanism. The development of genome-wide technologies and sophisticated statistical analytical approaches has ushered in an era of widespread analyses, for example in the cancer arena, of the relationships between altered DNA CpG methylation, gene expression, and tumor status. The remarkable increase in the volume of such genomic data, for example, through investigators from the Cancer Genome Atlas (TCGA), has allowed dissection of the relationships between DNA CpG methylation density and distribution, gene expression, and tumor outcome. In this manner, it is now possible to test that the genome-wide correlations are measurable between changes in DNA CpG methylation and gene expression. Perhaps surprisingly is that these associations can only be detected for hundreds, but not thousands, of genes, and the direction of the correlations are both positive and negative. This, perhaps, suggests that CpG methylation events in cancer systems can act as disease drivers but the effects are possibly more restricted than suspected. Additionally, the positive and negative correlations suggest direct and indirect events and an incomplete understanding. Within the prostate cancer TCGA cohort, we examined the relationships between expression of genes that control DNA methylation, known targets of DNA methylation and tumor status. This revealed that genes that control the synthesis of S-adenosyl-l-methionine (SAM) associate with altered expression of DNA methylation targets in a subset of aggressive tumors. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview Factors That Shape Eukaryotic tRNAomes:  Processing, Modification and Anticodon–Codon Use
Biomolecules 2017, 7(1), 26; doi:10.3390/biom7010026
Received: 9 January 2017 / Accepted: 24 February 2017 / Published: 8 March 2017
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Abstract
Transfer RNAs (tRNAs) contain sequence diversity beyond their anticodons and the large variety of nucleotide modifications found in all kingdoms of life. Some modifications stabilize structure and fit in the ribosome whereas those to the anticodon loop modulate messenger RNA (mRNA) decoding activity
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Transfer RNAs (tRNAs) contain sequence diversity beyond their anticodons and the large variety of nucleotide modifications found in all kingdoms of life. Some modifications stabilize structure and fit in the ribosome whereas those to the anticodon loop modulate messenger RNA (mRNA) decoding activity more directly. The identities of tRNAs with some universal anticodon loop modifications vary among distant and parallel species, likely to accommodate fine tuning for their translation systems. This plasticity in positions 34 (wobble) and 37 is reflected in codon use bias. Here, we review convergent evidence that suggest that expansion of the eukaryotic tRNAome was supported by its dedicated RNA polymerase III transcription system and coupling to the precursor‐tRNA chaperone, La protein. We also review aspects of eukaryotic tRNAome evolution involving G34/A34 anticodon‐sparing, relation to A34 modification to inosine, biased codon use and regulatory information in the redundancy (synonymous) component of the genetic code. We then review interdependent anticodon loop modifications involving position 37 in eukaryotes. This includes the eukaryote‐specific tRNA modification, 3‐methylcytidine‐32 (m3C32) and the responsible gene, TRM140 and homologs which were duplicated and subspecialized for isoacceptor‐specific substrates and dependence on i6A37 or t6A37. The genetics of tRNA function is relevant to health directly and as disease modifiers. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Alcohol, Adipose Tissue and Lipid Dysregulation
Biomolecules 2017, 7(1), 16; doi:10.3390/biom7010016
Received: 19 December 2016 / Accepted: 10 February 2017 / Published: 16 February 2017
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Abstract
Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids
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Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids in liver steatosis, alcohol also impacts other functions of adipose tissue and lipid metabolism. Lipid balance in response to long‐term alcohol intake favors adipose tissue loss and fatty acid efflux as lipolysis is upregulated and lipogenesis is either slightly decreased or unchanged. Study of the lipolytic and lipogenic pathways has identified several regulatory proteins modulated by alcohol that contribute to these effects. Glucose tolerance of adipose tissue is also impaired by chronic alcohol due to decreased glucose transporter‐4 availability at the membrane. As an endocrine organ, white adipose tissue (WAT) releases several adipokines that are negatively modulated following chronic alcohol consumption including adiponectin, leptin, and resistin. When these effects are combined with the enhanced expression of inflammatory mediators that are induced by chronic alcohol, a proinflammatory state develops within WAT, contributing to the observed lipodystrophy. Lastly, while chronic alcohol intake may enhance thermogenesis of brown adipose tissue (BAT), definitive mechanistic evidence is currently lacking. Overall, both WAT and BAT depots are impacted by chronic alcohol intake and the resulting lipodystrophy contributes to fat accumulation in peripheral organs, thereby enhancing the pathological state accompanying chronic alcohol use disorder. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessReview Biosynthesis of Sulfur-Containing tRNA Modifications: A Comparison of Bacterial, Archaeal, and Eukaryotic Pathways
Biomolecules 2017, 7(1), 27; doi:10.3390/biom7010027
Received: 1 February 2017 / Revised: 3 March 2017 / Accepted: 6 March 2017 / Published: 11 March 2017
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Abstract
Post-translational tRNA modifications have very broad diversity and are present in all domains of life. They are important for proper tRNA functions. In this review, we emphasize the recent advances on the biosynthesis of sulfur-containing tRNA nucleosides including the 2-thiouridine (s2U)
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Post-translational tRNA modifications have very broad diversity and are present in all domains of life. They are important for proper tRNA functions. In this review, we emphasize the recent advances on the biosynthesis of sulfur-containing tRNA nucleosides including the 2-thiouridine (s2U) derivatives, 4-thiouridine (s4U), 2-thiocytidine (s2C), and 2-methylthioadenosine (ms2A). Their biosynthetic pathways have two major types depending on the requirement of iron–sulfur (Fe–S) clusters. In all cases, the first step in bacteria and eukaryotes is to activate the sulfur atom of free l-cysteine by cysteine desulfurases, generating a persulfide (R-S-SH) group. In some archaea, a cysteine desulfurase is missing. The following steps of the bacterial s2U and s4U formation are Fe–S cluster independent, and the activated sulfur is transferred by persulfide-carrier proteins. By contrast, the biosynthesis of bacterial s2C and ms2A require Fe–S cluster dependent enzymes. A recent study shows that the archaeal s4U synthetase (ThiI) and the eukaryotic cytosolic 2-thiouridine synthetase (Ncs6) are Fe–S enzymes; this expands the role of Fe–S enzymes in tRNA thiolation to the Archaea and Eukarya domains. The detailed reaction mechanisms of Fe–S cluster depend s2U and s4U formation await further investigations. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Sulfur Modifications of the Wobble U34 in tRNAs and their Intracellular Localization in Eukaryotic Cells
Biomolecules 2017, 7(1), 17; doi:10.3390/biom7010017
Received: 13 January 2017 / Revised: 8 February 2017 / Accepted: 8 February 2017 / Published: 18 February 2017
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Abstract
The wobble uridine (U34) of transfer RNAs (tRNAs) for two-box codon recognition, i.e., tRNALysUUU, tRNAGluUUC, and tRNAGlnUUG, harbor a sulfur- (thio-) and a methyl-derivative structure at the second and fifth positions of
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The wobble uridine (U34) of transfer RNAs (tRNAs) for two-box codon recognition, i.e., tRNALysUUU, tRNAGluUUC, and tRNAGlnUUG, harbor a sulfur- (thio-) and a methyl-derivative structure at the second and fifth positions of U34, respectively. Both modifications are necessary to construct the proper anticodon loop structure and to enable them to exert their functions in translation. Thio-modification of U34 (s2U34) is found in both cytosolic tRNAs (cy-tRNAs) and mitochondrial tRNAs (mt-tRNAs). Although l-cysteine desulfurase is required in both cases, subsequent sulfur transfer pathways to cy-tRNAs and mt-tRNAs are different due to their distinct intracellular locations. The s2U34 formation in cy-tRNAs involves a sulfur delivery system required for the biosynthesis of iron-sulfur (Fe/S) clusters and certain resultant Fe/S proteins. This review addresses presumed sulfur delivery pathways for the s2U34 formation in distinct intracellular locations, especially that for cy-tRNAs in comparison with that for mt-tRNAs. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function
Biomolecules 2017, 7(1), 29; doi:10.3390/biom7010029
Received: 23 January 2017 / Revised: 6 March 2017 / Accepted: 6 March 2017 / Published: 16 March 2017
Cited by 1 | PDF Full-text (3670 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
RNAs are central to all gene expression through the control of protein synthesis. Four major nucleosides, adenosine, guanosine, cytidine and uridine, compose RNAs and provide sequence variation, but are limited in contributions to structural variation as well as distinct chemical properties. The ability
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RNAs are central to all gene expression through the control of protein synthesis. Four major nucleosides, adenosine, guanosine, cytidine and uridine, compose RNAs and provide sequence variation, but are limited in contributions to structural variation as well as distinct chemical properties. The ability of RNAs to play multiple roles in cellular metabolism is made possible by extensive variation in length, conformational dynamics, and the over 100 post-transcriptional modifications. There are several reviews of the biochemical pathways leading to RNA modification, but the physicochemical nature of modified nucleosides and how they facilitate RNA function is of keen interest, particularly with regard to the contributions of modified nucleosides. Transfer RNAs (tRNAs) are the most extensively modified RNAs. The diversity of modifications provide versatility to the chemical and structural environments. The added chemistry, conformation and dynamics of modified nucleosides occurring at the termini of stems in tRNA’s cloverleaf secondary structure affect the global three-dimensional conformation, produce unique recognition determinants for macromolecules to recognize tRNAs, and affect the accurate and efficient decoding ability of tRNAs. This review will discuss the impact of specific chemical moieties on the structure, stability, electrochemical properties, and function of tRNAs. Full article
(This article belongs to the Special Issue tRNA Modifications: Synthesis, Function and Beyond)
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Open AccessReview Common Chemical Inductors of Replication Stress: Focus on Cell‐Based Studies
Biomolecules 2017, 7(1), 19; doi:10.3390/biom7010019
Received: 25 November 2016 / Accepted: 10 February 2017 / Published: 21 February 2017
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Abstract
DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS). Owing to the
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DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS). Owing to the complexity and requirements of replication, a plethora of factors may interfere and challenge the genome stability, cell survival or affect the whole organism. This review outlines chemical compounds that are known inducers of RS and commonly used in laboratory research. These compounds act on replication by direct interaction with DNA causing DNA crosslinks and bulky lesions (cisplatin), chemical interference with the metabolism of deoxyribonucleotide triphosphates (hydroxyurea), direct inhibition of the activity of replicative DNA polymerases (aphidicolin) and interference with enzymes dealing with topological DNA stress (camptothecin, etoposide). As a variety of mechanisms can induce RS, the responses of mammalian cells also vary. Here, we review the activity and mechanism of action of these compounds based on recent knowledge, accompanied by examples of induced phenotypes, cellular readouts and commonly used doses. Full article
(This article belongs to the Special Issue Chromosome Maintenance)
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