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The molecular basis of tRNA selectivity by human pseudouridine synthase 3

Pseudouridine (Ψ), the isomer of uridine, is ubiquitously found in RNA, including tRNA, rRNA, and mRNA. Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs. However, the molecular mechanisms by which it recognizes its RNA targets and achieves site specificity...

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Main Authors: Lin, Ting-Yu (Author) , Kleemann, Leon (Author) , Jeżowski, Jakub (Author) , Dobosz, Dominika (Author) , Rawski, Michał (Author) , Indyka, Paulina (Author) , Ważny, Grzegorz (Author) , Mehta, Rahul (Author) , Chramiec-Głąbik, Andrzej (Author) , Koziej, Łukasz (Author) , Ranff, Tristan (Author) , Fufezan, Christian (Author) , Wawro, Mateusz (Author) , Kochan, Jakub (Author) , Bereta, Joanna (Author) , Leidel, Sebastian A. (Author) , Glatt, Sebastian (Author)
Format: Article (Journal)
Language:English
Published: 11 July 2024
In: Molecular cell
Year: 2024, Volume: 84, Issue: 13, Pages: 2472-2489,e1-e8
ISSN:1097-4164
DOI:10.1016/j.molcel.2024.06.013
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.molcel.2024.06.013
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1097276524005203
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Author Notes:Ting-Yu Lin, Leon Kleemann, Jakub Jeżowski, Dominika Dobosz, Michał Rawski, Paulina Indyka, Grzegorz Ważny, Rahul Mehta, Andrzej Chramiec-Głąbik, Łukasz Koziej, Tristan Ranff, Christian Fufezan, Mateusz Wawro, Jakub Kochan, Joanna Bereta, Sebastian A. Leidel, and Sebastian Glatt
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Summary:Pseudouridine (Ψ), the isomer of uridine, is ubiquitously found in RNA, including tRNA, rRNA, and mRNA. Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs. However, the molecular mechanisms by which it recognizes its RNA targets and achieves site specificity remain elusive. Here, we determine single-particle cryo-EM structures of PUS3 in its apo form and bound to three tRNAs, showing how the symmetric PUS3 homodimer recognizes tRNAs and positions the target uridine next to its active site. Structure-guided and patient-derived mutations validate our structural findings in complementary biochemical assays. Furthermore, we deleted PUS1 and PUS3 in HEK293 cells and mapped transcriptome-wide Ψ sites by Pseudo-seq. Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no evidence that human PUS3 modifies mRNAs. Our work provides the molecular basis for PUS3-mediated tRNA modification in humans and explains how its tRNA modification activity is linked to intellectual disabilities.
Item Description:Online verfügbar: 11. Juli 2024, Artikelversion: 11. Juli 2024
Gesehen am 28.01.2025
Physical Description:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2024.06.013

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