Please use this identifier to cite or link to this item:
http://dx.doi.org/10.25673/110781
Title: | Assembly defects of human tRNA splicing endonuclease contribute to impaired pre-tRNA processing in pontocerebellar hypoplasia |
Author(s): | Sekulovski, Samoil Devant, Pascal Caprioglio Panizza, Silvia ![]() Gogakos, Tasos Pitiriciu, Anda Heitmeier, Katharina Ramsay, Ewan Phillip Barth, Marie ![]() Schmidt, Carla ![]() Tuschl, Thomas ![]() Baas, Frank Weitzer, Stefan Martinez, Javier Trowitzsch, Simon ![]() |
Issue Date: | 2021 |
Type: | Article |
Language: | English |
Abstract: | Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes. |
URI: | https://opendata.uni-halle.de//handle/1981185920/112736 http://dx.doi.org/10.25673/110781 |
Open Access: | ![]() |
License: | ![]() |
Journal Title: | Nature Communications |
Publisher: | Nature Publishing Group UK |
Publisher Place: | [London] |
Volume: | 12 |
Original Publication: | 10.1038/s41467-021-25870-3 |
Page Start: | 1 |
Page End: | 15 |
Appears in Collections: | Open Access Publikationen der MLU |
Files in This Item:
File | Description | Size | Format | |
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s41467-021-25870-3.pdf | 1.75 MB | Adobe PDF | ![]() View/Open |