Pseudouridine

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Pseudouridine

In addition to the standard ribonucleotides, many RNA molecules contain modified nucleotides formed post-transcriptionally. Pseudouridine is formed in the context of a polyribonucleotide chain by the isomerization of uridine into pseudouridine and is the most abundant of these non-standard ribonucleotides. For that reason, it is sometimes referred to as the 'fifth ribonucleotide' of RNA, along with adenosine (A), guanosine(G), uridine (U) and cytidine(C) monophosphates.

Note: pseudouridine, as well as uridine, adenosine, cytidine and guanosine are nucleosides. The respective nucleotides are their monophosphates. It is nucleotides that constitute the monomer units in a nucleic acid (a polynucleotide). Their one-letter abbreviation is frequently used when referring either to the base or the nucleoside, as well as to the nucleotide when it is part of a nucleic acid (i.e. describing the sequence of the nucleic acid).

In contrast to the formation of several other types of modifications where moieties are added covalently to the bases or backbone, the formation of pseudouridine from uridine is mechanistically rather complex. In order to form this modified nucleotide, the base has to be removed from the uridine monophospate, rotated, and covalently rebonded to form pseudouridine.

Most tRNAs contain modified nucleotides[1], which are generated post-transcriptionally by specific enzymes. Archaeal and eukaryotic rRNAs are well known to be targets of guided pseudouridine formation by protein-small RNA complexes. However, recent studies have revealed many more pseudouridines exist in messenger RNA in humans than appreciated before[2][3][4].

Representation

An uppercase greek character Ψ, known as 'Psi', is often used to symbolically represent 'pseudouridine' or its monophosphate as a single character, especially when using it along with 'A', 'C', 'G' and 'U' for the standard ribonucleotides.

base nucleoside nucleotide
adenine, Ade, A adenosine, Ado, A adenylate, adenosine monophosphate, AMP, A
guanine, Gua, G guanosine, Guo, G guanylate, guanosine monophosphate, GMP, G
cytosine, Cyt, C cytidine, Cyd, C cytidylate, cytidine monophosphate, CMP, C
thymine, Thy, T thymidine, Thd, T thymidylate, thymidine monophosphate, TMP, T
uracyl, Ura, U uridine, Urd, U

pseudouridine, Ψrd, Ψ

uridylate, uridine monophosphate, UMP, U

pseudouridylate, pseudouridine monophosphate, Ψ

hypoxanthine, Hyp inosine, Ino, I inosinate, inosine monophosphate, IMP, I

(Similarly for deoxynucleosides and deoxynucleotides. The 3-letter abbreviations are those recommended by IUBMB and IUPAC[5][6])

Enzymatic Synthesis

See Pseudouridine synthase.

Disease

Pseudouridines have been implicated in several human diseases, such as X-linked dyskeratosis congenita, mitochondrial myopathy, and sideroblastic anemia; however, because of critical roles of the molecules being modified a direct causal link has remained to be defined[7]. With the finding of pseudouridine in many more locations among human RNAs in the last few years, there will be even more interest in relating these modifications to roles in pathologies[8].

See also

References

  1. Motorin Y, Helm M. tRNA stabilization by modified nucleotides. Biochemistry. 2010 Jun 22;49(24):4934-44. PMID:20459084 doi:10.1021/bi100408z
  2. Carlile TM, Rojas-Duran MF, Zinshteyn B, Shin H, Bartoli KM, Gilbert WV. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature. 2014 Nov 6;515(7525):143-6. doi: 10.1038/nature13802. Epub 2014 Sep 5. PMID:25192136 doi:http://dx.doi.org/10.1038/nature13802
  3. Zhao BS, He C. Pseudouridine in a new era of RNA modifications. Cell Res. 2015 Feb;25(2):153-4. doi: 10.1038/cr.2014.143. Epub 2014 Nov 4. PMID:25367125 doi:http://dx.doi.org/10.1038/cr.2014.143
  4. Adachi H, De Zoysa MD, Yu YT. Post-transcriptional pseudouridylation in mRNA as well as in some major types of noncoding RNAs. Biochim Biophys Acta Gene Regul Mech. 2018 Nov 8. pii: S1874-9399(18)30194-9., doi: 10.1016/j.bbagrm.2018.11.002. PMID:30414851 doi:http://dx.doi.org/10.1016/j.bbagrm.2018.11.002
  5. . IUPAC-IUB Commission on Biochemical Nomenclature (CBN). Abbreviations and symbols for nucleic acids, polynucleotides and their constituents. Recommendations 1970. Eur J Biochem. 1970 Aug;15(2):203-8. PMID:5502660
  6. . Nomenclature for incompletely specified bases in nucleic acid sequences. Recommendations 1984. Nomenclature Committee of the International Union of Biochemistry (NC-IUB). Proc Natl Acad Sci U S A. 1986 Jan;83(1):4-8. PMID:2417239
  7. Spenkuch F, Motorin Y, Helm M. Pseudouridine: still mysterious, but never a fake (uridine)! RNA Biol. 2014;11(12):1540-54. doi: 10.4161/15476286.2014.992278. PMID:25616362 doi:http://dx.doi.org/10.4161/15476286.2014.992278
  8. Rintala-Dempsey AC, Kothe U. Eukaryotic stand-alone pseudouridine synthases - RNA modifying enzymes and emerging regulators of gene expression? RNA Biol. 2017 Sep 2;14(9):1185-1196. doi: 10.1080/15476286.2016.1276150. Epub, 2017 Jan 3. PMID:28045575 doi:http://dx.doi.org/10.1080/15476286.2016.1276150

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