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Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing.
Genome Biol. 21:299 (2020)
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
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
ISSN (print) / ISBN
1474-760X
e-ISSN
1465-6906
Zeitschrift
Genome Biology
Quellenangaben
Band: 21,
Heft: 1,
Artikelnummer: 299
Verlag
BioMed Central
Verlagsort
Campus, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen
Bundesministerium für Bildung und Forschung
Deutsche Forschungsgemeinschaft
Austrian Science Fund
Deutsche Forschungsgemeinschaft
Austrian Science Fund