Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing

Author:

Hoser Simon M.ORCID,Hoffmann Anne,Meindl Andreas,Gamper Maximilian,Fallmann Jörg,Bernhart Stephan H.,Müller Lisa,Ploner Melanie,Misslinger Matthias,Kremser Leopold,Lindner Herbert,Geley Stephan,Schaal Heiner,Stadler Peter F.,Huettenhofer Alexander

Abstract

Abstract 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.

Funder

Austrian Science Fund

Deutsche Forschungsgemeinschaft

Bundesministerium für Bildung und Forschung

Jürgen Manchot Stiftung

Publisher

Springer Science and Business Media LLC

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