期刊
WILEY INTERDISCIPLINARY REVIEWS-RNA
卷 13, 期 5, 页码 -出版社
WILEY
DOI: 10.1002/wrna.1717
关键词
CLP1; PCH; tRNA processing; tRNA splicing; TSEN complex
类别
资金
- US National Institute of Health Intramural Research Program
- US National Institute of Environmental Health Sciences [ZIA ES103247]
- US National Institute of Health Extramural Research Program
- US National Institute of General Medical Sciences through the NIH Maximizing Opportunities for Scientific and Academic Independent Careers K99/R00 Pathway to Independence Award [1K99-GM143534]
- NIEHS Scholars Connect Program (NSCP)
- NIEHS
The splicing of tRNA introns is crucial for tRNA maturation in eukaryotes. The TSEN complex initiates the splicing process and mutations in its subunits are associated with PCH. Recent studies have provided insights into the structure, function, and regulation of the TSEN complex and shed light on how mutations in it contribute to neurodegenerative disease.
The splicing of transfer RNA (tRNA) introns is a critical step of tRNA maturation, for intron-containing tRNAs. In eukaryotes, tRNA splicing is a multi-step process that relies on several RNA processing enzymes to facilitate intron removal and exon ligation. Splicing is initiated by the tRNA splicing endonuclease (TSEN) complex which catalyzes the excision of the intron through its two nuclease subunits. Mutations in all four subunits of the TSEN complex are linked to a family of neurodegenerative and neurodevelopmental diseases known as pontocerebellar hypoplasia (PCH). Recent studies provide molecular insights into the structure, function, and regulation of the eukaryotic TSEN complex and are beginning to illuminate how mutations in the TSEN complex lead to neurodegenerative disease. Using new advancements in the prediction of protein structure, we created a three-dimensional model of the human TSEN complex. We review functions of the TSEN complex beyond tRNA splicing by highlighting recently identified substrates of the eukaryotic TSEN complex and discuss mechanisms for the regulation of tRNA splicing, by enzymes that modify cleaved tRNA exons and introns. Finally, we review recent biochemical and animal models that have worked to address the mechanisms that drive PCH and synthesize these studies with previous studies to try to better understand PCH pathogenesis. This article is categorized under: RNA Processing > tRNA Processing RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition
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