The quest for pseudouridine in mRNA: A six-decade pursuit of RNA’s pioneering modification

OTHER VIDEOS YOU MIGHT LIKE:
• The structure of RNA polymerase I: A 50 year mystery solved! - • The structure of RNA p...
• 5-Bromouracil: villian or hero? Mutagenesis with 5-bromouracil in bacteriophages - • 5-Bromouracil: villian...
• Shedding light on operons: Gene structure enabling the coregulation of structural genes - • Shedding light on oper...
The realization that RNA could undergo natural post-transcriptional modifications marked a significant milestone in the realm of genetics. This breakthrough challenged the notion that once DNA was transcribed into RNA, it remained unalterable, emphasizing the potential for changes that could influence protein translation. This pivotal mechanism was first uncovered in the context of pseudouridine, now recognized as the most prevalent nucleoside modification in RNA. Pseudouridine represents a modified version of uridine, one of the four fundamental nucleotides constituting RNA's foundational building blocks.
With advancements in sequencing technology and genetic databases, in 2014 Carlile and colleagues unveiled the presence of pseudouridine within mRNA. The researchers pioneered a technique for the high-resolution identification of pseudouridine sites within the transcriptome, coining it 'Pseudo-seq.' Through this method, they identified hundreds of naturally occurring pseudouridine sites in yeast and mammalian cells. Their investigations revealed that pseudouridylation was subject to regulation in response to environmental stimuli. The revelation of where pseudouridine is located within RNA paves the way for in-depth explorations into the biological processes underpinning this nucleoside. Further comprehension of diseases associated with dysregulated mRNA pseudouridine enzymes can be achieved, potentially offering avenues for treatment as research progresses. While the journey thus far has been lengthy, the path ahead remains extensive. However, the continued interest in this field has surged, notably fuelled by the fundamental and inspiring role of pseudouridine in the development of the COVID-19 vaccine.
Creator: Jack Peters
References:
Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Carlile TM, Rojas-Duran MF, Zinshteyn B, Shin H, Bartoli KM, Gilbert WV. Nature. 2014;515(7525):143-146. doi:10.1038/nature13802
Nucleoside-5′-phosphates from ribonucleic acid.
Cohn W, Volkin E. Nature 167, 483-484 (1951). doi.org/10.103...
An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Brenner, S, Jacob, F, Meselson, M. Nature 190, 576-581 (1961). doi.org/10.103...
Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Desrosiers R, Friderici K, Rottman F. Proc Natl Acad Sci U S A. 1974;71(10):3971-3975. doi:10.1073/pnas.71.10.3971
Four newly located pseudouridylate residues in Escherichia coli 23S ribosomal RNA are all at the peptidyltransferase center: analysis by the application of a new sequencing technique. Bakin A, Ofengand J. Biochemistry. 1993;32(37):9754-9762. doi:10.1021/bi00088a030
mRNA is an endogenous ligand for Toll-like receptor 3. Karikó K, Ni H, Capodici J, Lamphier M, Weissman D. J Biol Chem. 2004;279(13):12542-12550. doi:10.1074/jbc.M310175200
Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation. Patton JR, Bykhovskaya Y, Mengesha E, Bertolotto C, Fischel-Ghodsian N. J Biol Chem. 2005;280(20):19823-19828. doi:10.1074/jbc.M500216200
Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae. Lovejoy AF, Riordan DP, Brown PO. PLoS One. 2014;9(10):e110799. Published 2014 Oct 29. doi:10.1371/journal.pone.0110799
Transcriptome-wide analysis of pseudouridylation of mRNA and non-coding RNAs in Arabidopsis Sun L, Xu Y, Bai S, Bai X, Zhu H, Dong H, Wang W, Zhu X, Hao F, Song CP. J Exp Botany. 70(19), 5089-5600, doi.org/10.109...
Transcriptome-wide analysis of pseudouridylation in Drosophila melanogaster. Song W, Podicheti R, Rusch DB, Tracey WD. G3 (Bethesda). 2023 Mar 9;13(3):jkac333. doi: 10.1093/g3journal/jkac333. PMID: 36534986; PMCID: PMC9997552.
Pseudouridinylation of mRNA coding sequences alters translation. Eyler DE, Franco MK, Batool Z, Wu MZ, Dubuke ML, Dobosz-Bartoszek M, Jones JD, Polikanov YS, Roy B, Koutmou KS. Proc Natl Acad Sci U S A. 2019 Nov 12;116(46):23068-23074. doi: 10.1073/pnas.1821754116. Epub 2019 Oct 31. PMID: 31672910; PMCID:
Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Schwartz S, Bernstein DA, Mumbach MR, et al. Cell. 2014;159(1):148-162. doi:10.1016/j.cell.2014.08.028
Pseudouridine-mediated stop codon readthrough in S. cerevisiae is sequence context-independent. Adachi H, Yu YT RNA. 2020;26(9):1247-1256. doi:10.1261/rna.076042.120