Pseudouridine in RNA: What, Where, How, and Why

Charette, Michael W. Gray Michael

doi:10.1080/152165400410182

Cited by 469 publications

(215 citation statements)

References 62 publications

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“…In U1, U2, U4 and U6 snRNAs, for example, Ψ sites occur at or close to a site that basepairs with intronic RNA to facilitate RNA splicing (Charette and Gray, 2000). In rRNA there is a high density of conserved Ψ sites at the peptidyl-transferase center and at the decoding center of the 25S rRNA subunit, which interacts with mRNA and with the tRNA stem-loop (Bakin et al, 1994; Bakin and Ofengand, 1993; Lane et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…In yeast, Ψ is present in many positions in tRNAs, in 46 positions across the four rRNAs (25S, 18S, 5.8S, 5S), and in 6 positions in U1, U2 and U5 snRNA (Charette and Gray, 2000; Ofengand, 2002; Yu et al, 2011). Although ψ’s base pairing is similar to uridine, isomerization allows the potential formation of an extra hydrogen bond, and may contribute to structural stability (Durant and Davis, 1997; Kierzek et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA

Schwartz

Bernstein

Mumbach

et al. 2014

Cell

832

1,074

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SUMMARY Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here, we develop Ψ-seq for transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with spike-ins and de novo identification of previously reported positions and discover hundreds of novel sites in human and yeast mRNAs and snoRNAs. Perturbing pseudouridine synthases (PUSs) uncovers which PUSs modify each site and their target sequence features. mRNA pseudouridinylation depends on both site-specific and snoRNA-guided PUSs. Upon heat shock in yeast, Pus7-mediated pseudouridylation is induced at >200 sites and Pus7 deletion decreases the levels of otherwise pseudouridylated mRNA, suggesting a role in enhancing transcript stability. rRNA pseudouridine stoichiometries are conserved, but reduced in cells from dyskeratosis congenita patients, where the PUS DKC1 is mutated. Our work identifies an enhanced, transcritome-wide scope for pseudouridine, and methods to dissect its underlying mechanisms and function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA

Schwartz

Bernstein

Mumbach

et al. 2014

Cell

832

1,074

View full text Add to dashboard Cite

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“…For example, H 2 O 2 is known to oxidize thiol groups in proteins such as thioredoxin (63), whereas reactive Mtz intermediates might have greater affinity for reduced cofactors (68) or nucleic acids (10). Although the importance of DNA damage in the mechanism of Mtz cytotoxicity is contested (10,12), the increased transcription of genes encoding a pseudouridine synthase (acting to stabilize structural RNAs) (69) and several DNA repair enzymes specifically following Mtz exposure in this study suggests selective sensitivity of nucleic acids to this drug. Indeed, DNA damage may be sufficient to arrest the cell cycle, as suggested by transcriptional downregulation of the mitotic regulator Mad2 under Mtz and previous reports of H2A phosphorylation after sublethal Mtz exposure (15,70,71).…”

Section: Discussionmentioning

confidence: 99%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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dUnderstanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and ␣-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control. Giardia duodenalis (synonyms, Giardia lamblia and Giardia intestinalis) is a parasitic protist of the vertebrate gastrointestinal tract and the most common parasite of humans (1). The vegetative life cycle stage (trophozoite) infects around 1 billion people and causes 200 to 300 million cases of diarrheal disease (giardiasis) each year (1). Infection with G. duodenalis is also associated with the development of chronic diseases such as irritable bowel syndrome, chronic fatigue, and diabetes (2). At present, only two major drug classes are available to treat giardiasis: nitroimidazoles, primarily metronidazole (Mtz), and benzimidazoles, such as albendazole (3,4). Resistance to Mtz is documented in treatment-resistant clinical isolates (5-8), and resistant lines can be generated in vitro (reviewed in reference 9).The mechanism of action of Mtz is relatively poorly understood. This compound is thought to diffuse into G. duodenalis trophozoites as an inactive prodrug, whereupon it is enzymatically reduced (activated), yielding reactive intermediates. Mtz intermediates are thought to kill trophozoites by oxidizing proteins, lipids, and DNA (10, 11); however, the relative importance of damage to different biomolecules for Mtz-induced cytotoxicity is contested (10, 12). Resistance to Mtz involves changes in enzyme expression which limit drug activation. Nitroreductase-1, thioredoxin reductase, and pyruvat...

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“…47 Studies are underway to map the transcriptomewide C and Nms in the 2 life stages of the parasite, since both modifications are known to confer structural rigidity on localized RNA structure. 49 Indeed, these 2 modifications influence the RNA structure by favoring the C3 0 -endoribose conformation, diminishing the distance between the bases and enhancing stacking, which contributes to RNA stability. 50 In Euglena, an organism that is evolutionarily related to trypanosomes, the LSU is fragmented to 14 pieces 51 and the degree of modification (350 modified nt on rRNA) is correlated with the level of rRNA fragmentation.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of small nucleolar RNAs ofLeishmania majorreveals a rich repertoire of RNAs involved in modification and processing of rRNA

et al. 2015

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(2015) Genome-wide analysis of small nucleolar RNAs of Leishmaniamajor reveals a rich repertoire of RNAs involved in modification and processing of rRNA, RNA Biology, 12:11, 1222-1255, DOI: 10.1080/15476286.2015 Trypanosomatids are protozoan parasites and the causative agent of infamous infectious diseases. These organisms regulate their gene expression mainly at the post-transcriptional level and possess characteristic RNA processing mechanisms. In this study, we analyzed the complete repertoire of Leishmania major small nucleolar (snoRNA) RNAs by performing RNA-seq analysis on RNAs that were affinity-purified using the C/D snoRNA core protein, SNU13, and the H/ ACA core protein, NHP2. This study revealed a large collection of C/D and H/ACA snoRNAs, organized in gene clusters generally containing both snoRNA types. Abundant snoRNAs were identified and predicted to guide trypanosomespecific rRNA cleavages. The repertoire of snoRNAs was compared to that of the closely related Trypanosoma brucei, and 80% of both C/D and H/ACA molecules were found to have functional homologues. The comparative analyses elucidated how snoRNAs evolved to generate molecules with analogous functions in both species. Interestingly, H/ACA RNAs have great flexibility in their ability to guide modifications, and several of the RNA species can guide more than one modification, compensating for the presence of single hairpin H/ACA snoRNA in these organisms. Placing the predicted modifications on the rRNA secondary structure revealed hypermodification regions mostly in domains which are modified in other eukaryotes, in addition to trypanosome-specific modifications.

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Pseudouridine in RNA: What, Where, How, and Why

Cited by 469 publications

References 62 publications

Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA

Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Genome-wide analysis of small nucleolar RNAs ofLeishmania majorreveals a rich repertoire of RNAs involved in modification and processing of rRNA

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