ArticleNature communications2021
Assembly defects of human tRNA splicing endonuclease contribute to impaired pre-tRNA processing in pontocerebellar hypoplasia.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 35 citations in OpenAlex.
- Pontocerebellar hypoplasia linked mutations of the deadenylase Target of EGR1 (TOE1) impair thermal stability, ribonuclease activity, and oligomerization.The Journal of biological chemistry · 2026Article
- The regulation, function and disease relevance of cytoplasmic tRNAs.Nature reviews. Molecular cell biology · 2026Review
- Enzymology of the metazoan tRNA ligase complex: a lifetime in cycles.Cellular and molecular life sciences : CMLS · 2026Review
- Generating cerebellar organoids from pluripotent stem cells.Disease models & mechanisms · 2026Review
- Biochemical characterizations of Pontocerebellar Hypoplasia linked mutations of Target of Egr1 (TOE1) reveal impacts on thermal stability, ribonuclease activity, and oligomerization.bioRxiv : the preprint server for biology · 2025Article
- Emerging roles of transfer RNA fragments in the CNS.Brain : a journal of neurology · 2025Review
- A non-syndromic orofacial cleft risk locus links tRNA splicing defects to neural crest cell pathologies.American journal of human genetics · 2025Article
- New insights into tRNA-derived small RNAs in human digestive diseases.Molecular biology reports · 2025Review
- RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease.Nucleic acids research · 2024Article
- Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.Disease models & mechanisms · 2024Article
- Recognition and cleavage mechanism of intron-containing pre-tRNA by human TSEN endonuclease complex.Nature communications · 2023Article
- New insights into RNA processing by the eukaryotic tRNA splicing endonuclease.The Journal of biological chemistry · 2023Review
- The life and times of a tRNA.RNA (New York, N.Y.) · 2023Review
- Structural basis of substrate recognition by human tRNA splicing endonuclease TSEN.Nature structural & molecular biology · 2023Article
- Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex.Nature structural & molecular biology · 2023Article
- Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk-Conferring Alleles on a Shared Target Gene, COLGALT2.Arthritis & rheumatology (Hoboken, N.J.) · 2023Article
- Captured: the elusive eukaryotic tRNA splicing enzyme.Nature structural & molecular biology · 2023Article
- An unknown essential function of tRNA splicing endonuclease is linked to the integrated stress response and intron debranching.Genetics · 2023Article
- The physiology of alternative splicing.Nature reviews. Molecular cell biology · 2023Review
- tRNA dysregulation and disease.Nature reviews. Genetics · 2022Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 5 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.