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Mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes (MELAS)
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The MELAS syndrome is the result of mutation in mitochondrial genes for tRNA [41]. The most common is A-to-G transition at position 3243 of the tRNALeu(UUR) (see Figure 51.1) [4, 5]. Approximately 80 percent of affected individuals have this mutation in the dihydrouridine loop of the gene [8, 16, 42–44]. The other common mutation, occurring in about 8.5 percent of individuals, is also in the tRNALeu(UUR) at 3271 in the anticodon, where there is a T-to-C transversion [7]. The G-to-A transversion at 3252 of the same gene has been reported in mitochondrial encephalopathy [45]. Another mutation in the dihydrouridine loop at nucleotide 3250 is a T-to-C transition [42]. Another mutation in this gene is an A-to-T change at position 3256 [46]. A 5814G in the tRNACys gene was reported in a patient with cardiomyopathy and myopathy [35].
Ecology
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Uridine photohydrates, namely 6-hydroxy-5,6-dihydrouridine, were the major products formed upon irradiation of the phage R17 with UV light at 280 nm, while cyclobutane-type pyrimidine dimerization did not occur to an appreciable extent (Cerutti et al. 1969; Remsen et al. 1970). The suppression of dimerization was the first indication that the RNA inside the phage is held in a rigid conformation in close contact with the phage protein. It was concluded therefore that uridine photohydrates represented a major part of the lethal damage caused by UV light in the phage R17 (Remsen et al. 1970). Only 5.3 uridine photohydrates in the total R17 genome were necessary and sufficient to decrease the translation of the R17 coat gene to 37% by the in vitro translation system (Remsen and Cerutti 1972). Generally, a unit length of phage RNA (in bases) was 2–3 times more sensitive than a unit length of DNA (in base pairs) with respect to the inactivation of messenger function (Ponta et al. 1979). Mattern et al. (1972) showed that cytidine photohydration occurred in the R17 RNA with 10–15 times lower efficiency than the uridine photohydration. The formation of uridine hydrates in the UV-irradiated MS2 phage was acknowledged by Yamada et al. (1973). Moreover, εN-(2-oxopyrimidyl-4)-lysine was found in the phage MS2 hydrolysates after UV irradiation at 254 nm or treatment with bisulfite because of the covalent cross-linkage of the RNA to the coat protein: the exocyclic amino group of the activated cytosine was substituted by the lysine ε-amino group of the protein (Budowsky et al. 1976).
Translation and Post-Translational Modifications During Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
tRNAs are the molecules that physically bring the amino acids onto the template codons of mRNAs bound to ribosomes. There is at least one tRNA for each codon which is translatable into an amino acid, but there is no tRNA for the stop codons UAA, UAG, and UGA. For several amino acids, for example glycine, alanine, valine, leucine, serine, and arginine, there are four to six isoacceptor tRNA species, and their relative abundance is correlated with the codon usage in the mRNAs.69 Sequences of a large number of tRNAs and their genes have been determined. All tRNAs are between 70 and 95 nucleotides long and can be folded into a cloverleaf secondary structure. A unique characteristic of tRNA is the presence of several modified nucleotides, which are found near and around the anti-codon loop. More than 50 modified nucleotides have been discovered in eukaryotic tRNAs and these include dihydrouridine (D), inosine (I), N6-isopentenyladenosine (i6A), queusine (Q), and wyosine (Y). Although the exact mechanisms are not known, these modified nucleotides in tRNA are considered to be involved in the recognition of codons.
Strategies for improving the specificity of siRNAs for enhanced therapeutic potential
Published in Expert Opinion on Drug Discovery, 2018
Aditya Kiran Gatta, Raghu Chandrashekhar Hariharapura, Nayanabhirama Udupa, Meka Sreenivasa Reddy, Venkata Rao Josyula
Several researchers have explored the option of backbone modification to increase the efficacy of the siRNA. The basic backbone containing the phosphodiester bonds is substituted with the phosphorothioate or the boranophosphate. This modification improved the serum stability of the siRNA [90]. Fomivirsen is marketed under the brand name Vitravene. It is an oligonucleotide drug consisting of a phosphorothioate modification. Interestingly, it is the only oligonucleotide that was approved by the FDA in 1998 to treat retinitis [103,104]. However, this drug is currently withdrawn [105]. This modification is studied in great detail as it has nuclease stability and reduces renal clearance by enhancing binding with plasma proteins and improves the pharmacokinetic profiles. Although it was observed to have significant nuclease stability, it had a negative impact on silencing the activity. The boranophosphate modification is a substitution with BH3 (borane moiety) in the position of nonbridging phosphate oxygen atom. Unlike the phosphorothioate modification, this modification retains the functionality and the serum nuclease stability [90]. Apart from the chemical modifications, other nucleoside modifications like dihydrouridine, pseudouridine, and 2ʹ-thiouridine were also evaluated for the potency of the siRNA [106]. Recently, a database ‘siRNAmod’ is developed, which provides information about 128 types of modifications and on more than 5000 chemically modified siRNAs and their biological activities. The database is maintained on the LAMP (Linux Apache MySQL PHP) software. This database provides good evidence for the experimentally validated siRNAs, but it is yet to integrate to the designing algorithm [107].
Quantifying RNA modifications by mass spectrometry: a novel source of biomarkers in oncology
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Amandine Amalric, Amandine Bastide, Aurore Attina, Armelle Choquet, Jerome Vialaret, Sylvain Lehmann, Alexandre David, Christophe Hirtz
m1A is one of the most promising circulating chemical marks for cancer diagnosis. Several studies using MS have found increased serum m1A in patients with cancers such as hepatocellular carcinoma [31], papillary thyroid cancer [32], esophageal adenocarcinoma [30] and colorectal cancer [29]. Chen et al. [31] suggested that increased m1A correlated with inflammatory stress or oxidative damage. Other nucleosides such as 5,6-dihydrouridine (D) in oral leukoplakia were also up-regulated in cancer [36].