Abstract
Naturally occurring RNA molecules contain a variety of chemically modified nucleosides derived from the four standard nucleosides: cytidine, adenosine, uridine, and guanosine. These modified nucleosides contribute to many cellular processes, including RNA processing, the stability of RNA structures, and the fidelity and efficiency of protein expression. Alterations in RNA modification underlay the translational defects in the mitochondrial disorders MELAS syndrome and MERRF syndrome. Till date, two enzymes directly involved in RNA modification, TRMU and PUS1, have been identified which when mutated reduce the content of modified nucleosides of different classes of RNAs leading to altered protein expression and RNA stability. The underlying processes and components of RNA modification are reviewed, along with descriptions of the clinical features associated with this unique class of disorders.
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References
Dunin-Horkawicz S, Czerwoniec A, Gajda MJ, Feder M, Grosjean H, Bujnicki JM (2006) MODOMICS: A database of RNA modification pathways. Nucleic Acids Res 34:D145–149
Anantharaman V, Koonin EV, Aravind L (2002) Comparative genomics and evolution of proteins involved in RNA metabolism. Nucleic Acids Res 30:1427–1464
Ishitani R, Yokoyama S, Nureki O (2008) Structure, dynamics, and function of RNA modification enzymes. Current opinion in structural biology 18:330–339
Waas WF, Druzina Z, Hanan M, Schimmel P (2007) Role of a tRNA base modification and its precursors in frameshifting in eukaryotes. J Biol Chem 282:26026–26034
Gallo A, Locatelli F (2012) ADARs: Allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1. Biol Rev Cambridge Philos Soc 87:95–110
Blanc V, Davidson NO (2011) Mouse and other rodent models of C to U RNA editing. Methods Mol Biol 718:121–135
Orlandi C, Barbon A, Barlati S (2012) Activity regulation of adenosine deaminases acting on RNA (ADARs). Mole Neurobiol 45:61–75
Tan BZ, Huang H, Lam R, Soong TW (2009) Dynamic regulation of RNA editing of ion channels and receptors in the mammalian nervous system. Mol Brain 2:13
Nishikura K (2010) Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79:321–349
Paris Z, Fleming IM, Alfonzo JD (2011) Determinants of tRNA editing and modification: Avoiding conundrums, affecting function. Semin Cell Dev Biol
Randau L, Stanley BJ, Kohlway A, Mechta S, Xiong Y, Soll D (2009) A cytidine deaminase edits C to U in transfer RNAs in Archaea. Sci 324:657–659
Ofengand J (2002) Ribosomal RNA pseudouridines and pseudouridine synthases. FEBS Lett 514:17–25
Madore E, Florentz C, Giege R, Sekine S, Yokoyama S, Lapointe J (1999) Effect of modified nucleotides on Escherichia coli tRNAGlu structure and on its aminoacylation by glutamyl-tRNA synthetase. Predominant and distinct roles of the mnm5 and s2 modifications of U34. Eur J Biochem FEBS 266:1128–1135
Kruger MK, Pedersen S, Hagervall TG, Sorensen MA (1998) The modification of the wobble base of tRNAGlu modulates the translation rate of glutamic acid codons in vivo. J Mol Biol 284:621–631
Urbonavicius J, Stahl G, Durand JM, Ben Salem SN, Qian Q, Farabaugh PJ, Bjork GR (2003) Transfer RNA modifications that alter + 1 frameshifting in general fail to affect−1 frameshifting. RNA 9:760–768
Kambampati R, Lauhon CT (2003) MnmA and IscS are required for in vitro 2-thiouridine biosynthesis in Escherichia coli. Biochem 42:1109–1117
Hagervall TG, Pomerantz SC, McCloskey JA (1998) Reduced misreading of asparagine codons by Escherichia coli tRNALys with hypomodified derivatives of 5-methylaminomethyl-2-thiouridine in the wobble position. J Mol Biol 284:33–42
Sullivan MA, Cannon JF, Webb FH, Bock RM (1985) Antisuppressor mutation in Escherichia coli defective in biosynthesis of 5-methylaminomethyl-2-thiouridine. J Bacteriol 161:368–376
Umeda N, Suzuki T, Yukawa M, Ohya Y, Shindo H, Watanabe K (2005) Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases. J Biol Chem 280:1613–1624
Wang X, Yan Q, Guan MX (2007) Deletion of the MTO2 gene related to tRNA modification causes a failure in mitochondrial RNA metabolism in the yeast Saccharomyces cerevisiae. FEBS Lett 581:4228–4234
Charette M, Gray MW (2000) Pseudouridine in RNA: What, where, how, and why. IUBMB Life 49:341–351
Guymon R, Pomerantz SC, Ison JN, Crain PF, McCloskey JA (2007) Post-transcriptional modifications in the small subunit ribosomal RNA from Thermotoga maritima, including presence of a novel modified cytidine. RNA 13:396–403
Reichow SL, Hamma T, Ferre-D’Amare AR, Varani G (2007) The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Res 35:1452–1464
Kiss T, Fayet-Lebaron E, Jady BE (2010) Box H/ACA small ribonucleoproteins. Mol Cell 37:597–606
Lin J, Lai S, Jia R, Xu A, Zhang L, Lu J, Ye K (2011) Structural basis for site-specific ribose methylation by box C/D RNA protein complexes. Nat 469:559–563
Hamma T, Ferre-D’Amare AR (2010) The box H/ACA ribonucleoprotein complex: interplay of RNA and protein structures in post-transcriptional RNA modification. J Biol Chem 285:805–809
Phillips G, de Crecy-Lagard V (2011) Biosynthesis and function of tRNA modifications in Archaea. Curr Opin Microbiol 14:335–341
Hamma T, Ferre-D’Amare AR (2006) Pseudouridine synthases. Chem Biol 13:1125–1135
Mason PJ, Bessler M (2011) The genetics of dyskeratosis congenital. Cancer Genet 204:635–645
Agris PF, Vendeix FA, Graham WD (2007) tRNA’s wobble decoding of the genome: 40 years of modification. J Mol Biol 366:1–13
Watanabe K, Yokobori S (2011) tRNA Modification and genetic code variations in animal mitochondria. J Nucleic Acids 2011:623095
Kirino Y, Suzuki T (2005) Human mitochondrial diseases associated with tRNA wobble modification deficiency. RNA Biol 2:41–44
Kirino Y, Yasukawa T, Ohta S, Akira S, Ishihara K, Watanabe K, Suzuki T (2004) Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc Nat Acad Sci U S A 101:15070–15075
Sasarman F, Antonicka H, Horvath R, Shoubridge EA (2011) The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation. Hum Mol Genet 20:4634–4643
Zeharia A, Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, Karicheva O, Mandel H, Ofek N, Segel R, Marom D, Rotig A, Tarassov I, Elpeleg O (2009) Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 85:401–407
Schara U, von Kleist-Retzow JC, Lainka E, Gerner P, Pyle A, Smith PM, Lochmuller H, Czermin B, Abicht A, Holinski-Feder E, Horvath R (2011) Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations. J Inherited Metab Dis 34:197–201
Lev D, Gilad E, Leshinsky-Silver E, Houri S, Levine A, Saada A, Lerman-Sagie T (2002) Reversible fulminant lactic acidosis and liver failure in an infant with hepatic cytochrome-c oxidase deficiency. J Inherited Metab Dis 25:371–377
Uusimaa J, Jungbluth H, Fratter C, Crisponi G, Feng L, Zeviani M, Hughes I, Treacy EP, Birks J, Brown GK, Sewry CA, McDermott M, Muntoni F, Poulton J (2011) Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J Med Genet 48:660–66839
Guan MX, Yan Q, Li X, Bykhovskaya Y, Gallo-Teran J, Hajek P, Umeda N, Zhao H, Garrido G, Mengesha E, Suzuki T, del Castillo I, Peters JL, Li R, Qian Y, Wang X, Ballana E, Shohat M, Lu J, Estivill X, Watanabe K, Fischel-Ghodsian N (2006) Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12 S ribosomal RNA mutations. Am J Hum Genet 79:291–302
Bergmann AK, Campagna DR, McLoughlin EM, Agarwal S, Fleming MD, Bottomley SS, Neufeld EJ (2010) Systematic molecular genetic analysis of congenital sideroblastic anemia: Evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer 54:273–278
Rawles JM, Weller RO (1974) Familial association of metabolic myopathy, lactic acidosis and sideroblastic anemia. Am J Med 56:891–897
Casas KA, Fischel-Ghodsian N (2004) Mitochondrial myopathy and sideroblastic anemia. Am J Med Genet Part A 125A:201–204
Zeharia A, Fischel-Ghodsian N, Casas K, Bykhocskaya Y, Tamari H, Lev D, Mimouni M, Lerman-Sagie T (2005) Mitochondrial myopathy, sideroblastic anemia, and lactic acidosis: an autosomal recessive syndrome in Persian Jews caused by a mutation in the PUS1 gene. J Child Neurol 20:449–452
Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N (2004) Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 74:1303–1308
Casas K, Bykhovskaya Y, Mengesha E, Wang D, Yang H, Taylor K, Inbal A, Fischel-Ghodsian N (2004) Gene responsible for mitochondrial myopathy and sideroblastic anemia (MSA) maps to chromosome 12q24.33. Am J Med Genet Part A 127A:44–49
Fernandez-Vizarra E, Berardinelli A, Valente L, Tiranti V, Zeviani M (2007) Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). J Med Genet 44:173–180
Colley SM, Leedman PJ (2011) Steroid Receptor RNA Activator – A nuclear receptor coregulator with multiple partners: Insights and challenges. Biochimie 93:1966–1972
Zhao X, Patton JR, Ghosh SK, Fischel-Ghodsian N, Shen L, Spanjaard RA (2007) Pus3p- and Pus1p-dependent pseudouridylation of steroid receptor RNA activator controls a functional switch that regulates nuclear receptor signaling. Mol Endocrinol 21:686–699
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Craigen, W. (2013). Disorders of Mitochondrial RNA Modification. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_18
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DOI: https://doi.org/10.1007/978-1-4614-3722-2_18
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