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An extended dsRBD is required for post-transcriptional modification in human tRNAs.

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Bou-Nader C, Pecqueur L, Bregeon D, Kamah A, Guérineau V, Golinelli-Pimpaneau B, Guimarães BG, Fontecave M, Hamdane D
OpenAccess logo Nucleic Acids Res 43 9446-56 (2015)
Cited: 11 times
EuropePMC logo PMID: 26429968

Abstract

In tRNA, dihydrouridine is a conserved modified base generated by the post-transcriptional reduction of uridine. Formation of dihydrouridine 20, located in the D-loop, is catalyzed by dihydrouridine synthase 2 (Dus2). Human Dus2 (HsDus2) expression is upregulated in lung cancers, offering a growth advantage throughout its ability to interact with components of the translation apparatus and inhibit apoptosis. Here, we report the crystal structure of the individual domains of HsDus2 and their functional characterization. HsDus2 is organized into three major modules. The N-terminal catalytic domain contains the flavin cofactor involved in the reduction of uridine. The second module is the conserved α-helical domain known as the tRNA binding domain in HsDus2 homologues. It is connected via a flexible linker to an unusual extended version of a dsRNA binding domain (dsRBD). Enzymatic assays and yeast complementation showed that the catalytic domain binds selectively NADPH but cannot reduce uridine in the absence of the dsRBD. While in Dus enzymes from bacteria, plants and fungi, tRNA binding is essentially achieved by the α-helical domain, we showed that in HsDus2 this function is carried out by the dsRBD. This is the first reported case of a tRNA-modifying enzyme carrying a dsRBD used to bind tRNAs.

Articles - 4wfs mentioned but not cited (2)

  1. An extended dsRBD is required for post-transcriptional modification in human tRNAs. Bou-Nader C, Pecqueur L, Bregeon D, Kamah A, Guérineau V, Golinelli-Pimpaneau B, Guimarães BG, Fontecave M, Hamdane D. Nucleic Acids Res 43 9446-9456 (2015)
  2. Evolutionary Diversity of Dus2 Enzymes Reveals Novel Structural and Functional Features among Members of the RNA Dihydrouridine Synthases Family. Lombard M, Reed CJ, Pecqueur L, Faivre B, Toubdji S, Sudol C, Brégeon D, de Crécy-Lagard V, Hamdane D. Biomolecules 12 1760 (2022)


Reviews citing this publication (4)

  1. Human transfer RNA modopathies: diseases caused by aberrations in transfer RNA modifications. Chujo T, Tomizawa K. FEBS J 288 7096-7122 (2021)
  2. The search for a PKR code-differential regulation of protein kinase R activity by diverse RNA and protein regulators. Bou-Nader C, Gordon JM, Henderson FE, Zhang J. RNA 25 539-556 (2019)
  3. The Dihydrouridine landscape from tRNA to mRNA: a perspective on synthesis, structural impact and function. Finet O, Yague-Sanz C, Marchand F, Hermand D. RNA Biol 19 735-750 (2022)
  4. Modopathies Caused by Mutations in Genes Encoding for Mitochondrial RNA Modifying Enzymes: Molecular Mechanisms and Yeast Disease Models. Magistrati M, Gilea AI, Ceccatelli Berti C, Baruffini E, Dallabona C. Int J Mol Sci 24 2178 (2023)

Articles citing this publication (5)

  1. Unveiling structural and functional divergences of bacterial tRNA dihydrouridine synthases: perspectives on the evolution scenario. Bou-Nader C, Montémont H, Guérineau V, Jean-Jean O, Brégeon D, Hamdane D. Nucleic Acids Res 46 1386-1394 (2018)
  2. HIV-1 matrix-tRNA complex structure reveals basis for host control of Gag localization. Bou-Nader C, Muecksch F, Brown JB, Gordon JM, York A, Peng C, Ghirlando R, Summers MF, Bieniasz PD, Zhang J. Cell Host Microbe 29 1421-1436.e7 (2021)
  3. Molecular basis for transfer RNA recognition by the double-stranded RNA-binding domain of human dihydrouridine synthase 2. Bou-Nader C, Barraud P, Pecqueur L, Pérez J, Velours C, Shepard W, Fontecave M, Tisné C, Hamdane D. Nucleic Acids Res 47 3117-3126 (2019)
  4. Dihydrouridine synthesis in tRNAs is under reductive evolution in Mollicutes. Faivre B, Lombard M, Fakroun S, Vo CD, Goyenvalle C, Guérineau V, Pecqueur L, Fontecave M, De Crécy-Lagard V, Brégeon D, Hamdane D. RNA Biol 18 2278-2289 (2021)
  5. De novo crystal structure determination of double stranded RNA binding domain using only the sulfur anomalous diffraction in SAD phasing. Guimarães BG, Golinelli-Pimpaneau B. Curr Res Struct Biol 3 112-120 (2021)


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