Mechanisms and Clinical Applications of RNA Pseudouridylation

Morais, Pedro; Adachi, Hironori; Chen, Jonathan L.; Yu, Yi‐Tao

doi:10.1007/978-3-030-71612-7_19

Cited by 3 publications

(6 citation statements)

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“…[86] The gRNAs generally interacted with their substrates via eight to 12 Watson-Crick pairs (Figure 2E), zero to two GU pairs, and no mismatches. In rRNA, 65 The crystal structure of a catalytically active archaeal (Archaeoglobus fulgidus) C/D RNP, consisting of a bipartite C/D RNA associated with substrate RNA, Nop5 (Nop56/58 in eukaryotes), L7Ae and fibrillarin, has been solved at 3.15-Å resolution. [87] It showed that fibrillarin bound to an undistorted A-form guide-substrate duplex and lead the target nucleotide (paired to the fifth nucleotide of the guide, counting from box D or D') to its catalytic center (Figure 3D).…”

Section: Structure and Function Of Box C/d Snornpmentioning

confidence: 99%

RNA‐Guided RNA Pseudouridylation and 2’‐O‐Methylation

Adachi,

Chen,

Leeder

et al. 2024

Israel Journal of Chemistry

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RNA‐guided RNA modifications, including pseudouridylation and 2′‐O‐methylation, are naturally occurring processes that introduce pseudouridines (Ψ) and 2’‐O‐methylated residues (2’‐O−Me) into various types of RNA. This modification is orchestrated by two distinct families of ribonucleoprotein complexes: Box H/ACA RNP and Box C/D RNP. Each complex comprises a unique guide (g)RNA (Box H/ACA gRNA or Box C/D gRNA) and a set of core proteins responsible for pseudouridylation and 2’‐O‐methylation, respectively. The specificity of these modifications is conferred by base‐pairing of Box H/ACA gRNA and Box C/D gRNA with their RNA substrates. Here, we discuss the mechanism and function of RNA‐guided pseudouridylation and 2’‐O‐methylation.

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Section: Structure and Function Of Box C/d Snornpmentioning

confidence: 99%

RNA‐Guided RNA Pseudouridylation and 2’‐O‐Methylation

Adachi,

Chen,

Leeder

et al. 2024

Israel Journal of Chemistry

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“…Pseudouridylation can be either catalyzed by stand-alone protein enzymes (pseudouridylases) or by large RNA-Protein complexes called H/ACA box snoRNPs, where the RNA components serve as guides to direct site-specific pseudouridylation ( Morais et al, 2021 ). Since Ψ is highly conserved and known to perform essential functions in the cell, several known diseases are associated with defects in RNA pseudouridylation.…”

Section: ψ Is An Abundant Naturally Occurring Modified Nucleotide Found In Many Types Of Rnamentioning

confidence: 99%

“…Also, because pseudouridylation appears to be irreversible, Ψ is usually excreted from the body. Thus, this RNA modification has drawn attention as a potential biomarker for Alzheimer’s disease and certain types of cancer ( Morais et al, 2021 ).…”

Section: ψ Is An Abundant Naturally Occurring Modified Nucleotide Found In Many Types Of Rnamentioning

confidence: 99%

“…This N1-methylation is catalyzed by N1-specific Ψ methyltransferase Nep1 found in archaea and eukaryotes ( Wurm et al, 2010 ) ( Figure 1 ). Potentially N1-methyl-Ψ could be more widespread than reported in human RNA, given that the current standard Ψ-detection (-seq) methods, which rely on the use of CMC-modification followed by primer extension ( Morais et al, 2021 ), may not be able to distinguish N1-methyl-Ψ from Ψ ( Svitkin et al, 2017 ). Possibly, therefore, some Ψs thus identified so far ( Schwartz et al, 2014 ) could actually be N1-methylated Ψs.…”

Section: N1-methylated ψ Behaves Better Than ψmentioning

confidence: 99%

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The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines

Morais

Adachi

2021

Front. Cell Dev. Biol.

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The current COVID-19 pandemic is a massive source of global disruption, having led so far to two hundred and fifty million COVID-19 cases and almost five million deaths worldwide. It was recognized in the beginning that only an effective vaccine could lead to a way out of the pandemic, and therefore the race for the COVID-19 vaccine started immediately, boosted by the availability of the viral sequence data. Two novel vaccine platforms, based on mRNA technology, were developed in 2020 by Pfizer-BioNTech and Moderna Therapeutics (comirnaty® and spikevax®, respectively), and were the first ones presenting efficacies higher than 90%. Both consisted of N1-methyl-pseudouridine-modified mRNA encoding the SARS-COVID-19 Spike protein and were delivered with a lipid nanoparticle (LNP) formulation. Because the delivery problem of ribonucleic acids had been known for decades, the success of LNPs was quickly hailed by many as the unsung hero of COVID-19 mRNA vaccines. However, the clinical trial efficacy results of the Curevac mRNA vaccine (CVnCoV) suggested that the delivery system was not the only key to the success. CVnCoV consisted of an unmodified mRNA (encoding the same spike protein as Moderna and Pfizer-BioNTech’s mRNA vaccines) and was formulated with the same LNP as Pfizer-BioNTech’s vaccine (Acuitas ALC-0315). However, its efficacy was only 48%. This striking difference in efficacy could be attributed to the presence of a critical RNA modification (N1-methyl-pseudouridine) in the Pfizer-BioNTech and Moderna’s mRNA vaccines (but not in CVnCoV). Here we highlight the features of N1-methyl-pseudouridine and its contributions to mRNA vaccines.

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“…[3][4][5] Ψ is one of the most abundant, and it plays a role in ribosomal RNA translational fidelity, mRNA splicing in small nuclear RNAs, and the stabilization of RNA structures via a bifurcated hydrogen bond. [62][63][64][65] Distinguishing between Ψ and uracil is difficult due to their structural similarity, until it was discovered that Ncyclohexyl-N'-b-(4-methylmorpholinium) ethylcarbodiimide (CMC) could be used to label Ψ, thereby realizing the distinction specifically. 66,67 Chengqi Yi et al achieved the selective labeling of Ψ by synthesizing N3-CMC while modifying azide on Ψ to obtain N3-CMC-Ψ, realizing the biotinylation of Ψ through a click reaction.…”

Section: Chemical Labeling In Rnamentioning

confidence: 99%