Spatial regulation of NSUN2-mediated tRNA m5C installation in cognitive function.

Autor:	Gonskikh Y; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Tirrito C; Biology Graduate Group, University of Pennsylvania, School of Arts and Sciences, Philadelphia, PA 19104, USA.; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Bommisetti P; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Mendoza-Figueroa MS; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Stoute J; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Kim J; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Wang Q; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Song Y; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Liu KF; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA 19104, USA.; Penn Center for Genome Integrity, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 Dec 14. Date of Electronic Publication: 2024 Dec 14.
DOI:	10.1093/nar/gkae1169
Abstrakt:	Enzyme-mediated modifications of tRNA, such as 5-methylcytosine (m5C) installed by nuclear-enriched NOP2/Sun RNA methyltransferase 2 (NSUN2), play a critical role in neuronal development and function. However, our understanding of these modifications' spatial installation and biological functions remains incomplete. In this study, we demonstrate that a nucleoplasm-localized G679R NSUN2 mutant, linked to intellectual disability, diminishes NSUN2-mediated tRNA m5C in human cell lines and Drosophila. Our findings indicate that inability of G679R-NSUN2 to install m5C is primarily attributed to its reduced binding to tRNA rather than its nucleoplasmic localization. Conversely, an NSUN2 variant lacking an internal intrinsically disordered region (ΔIDR-NSUN2) can install ∼80% m5C within the nucleoplasm. Furthermore, we show that tRNA m5C levels are positively correlated to cognitive performance in Drosophila, where expressing G679R-NSUN2 leads to the most severe social behavioral deficits while expressing ΔIDR-NSUN2 results in less pronounced deficits. This work illuminates the molecular mechanism underlying G679R disease mutation in cognitive function and offers valuable insights into the significance of the cellular localization of m5C installation on tRNA for neuronal function. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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