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Hoser, S.M.* ; Hoffmann, A. ; Meindl, A.* ; Gamper, M.* ; Fallmann, J.* ; Bernhart, S.H.* ; Müller, L.* ; Ploner, M.* ; Misslinger, M.* ; Kremser, L.* ; Lindner, H.* ; Geley, S.* ; Schaal, H.* ; Stadler, P.F.* ; Huettenhofer, A.*

Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing.

Genome Biol. 21:299 (2020)
Publ. Version/Full Text DOI PMC
Open Access Gold
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Background: The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein-coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA remain elusive. Results: Employing in silico analysis, we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on the number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach, we show that a partial deletion of a single endogenous nimtRNALys within intron 28 of the PPFIBP1 gene decreases inclusion of the downstream-located exon 29 of the PPFIBP1 mRNA. By employing a pull-down approach followed by mass spectrometry, a 3′-splice site-associated protein network is identified, including KHDRBS1, which we show directly interacts with nimtRNATyr by an electrophoretic mobility shift assay. Conclusions: We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alternative Splicing ; Constitutive Splicing ; Intronic Splicing Enhancer (ise) ; Mitochondrial Trna ; Nimtrna ; Numtdna ; Splicing ; Splicing Regulatory Element ; Trna ; Trna-lookalikes; Binding-sites; H/aca Snornas; Insights; Protein; Activation; Mechanisms; Evolution; Nuclear; Transcription; Organization
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1474-760X
e-ISSN 1465-6906
Journal Genome Biology
Quellenangaben Volume: 21, Issue: 1, Pages: , Article Number: 299 Supplement: ,
Publisher BioMed Central
Publishing Place Campus, 4 Crinan St, London N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-506501-001
Grants Bundesministerium für Bildung und Forschung
Deutsche Forschungsgemeinschaft
Austrian Science Fund
DOI 10.1186/s13059-020-02199-6
WOS ID WOS:000600100800005
Scopus ID 85097266999
PubMed ID 33292386
Erfassungsdatum 2020-12-14
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