Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria

• Published in: Nature communications Vol. 9; no. 1; pp. 2558 - 15
• Main Authors: Pietras, Zbigniew, Wojcik, Magdalena A., Borowski, Lukasz S., Szewczyk, Maciej, Kulinski, Tomasz M., Cysewski, Dominik, Stepien, Piotr P., Dziembowski, Andrzej, Szczesny, Roman J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/89; 14/63; 38/91; 631/208/199; 631/337/1645/1769; 631/337/1645/2020; 631/80/642/333; Animals; Biological evolution; Cooperation; Cooperativity; DEAD-box RNA Helicases - metabolism; Degradation; Endoribonucleases - metabolism; Exoribonucleases - genetics; Exoribonucleases - metabolism; G-Quadruplexes; Genome, Mitochondrial - genetics; Genomes; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; multidisciplinary; Multienzyme Complexes - metabolism; Phylogeny; Poly(A)-Binding Proteins - genetics; Poly(A)-Binding Proteins - metabolism; Polyribonucleotide Nucleotidyltransferase - metabolism; Post-transcription; Proteins; Ribonucleic acid; RNA; RNA Helicases - metabolism; RNA, Small Interfering - metabolism; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; Science; Science (multidisciplinary); Vertebrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05007-9

The GC skew in vertebrate mitochondrial genomes results in synthesis of RNAs that are prone to form G-quadruplexes (G4s). Such RNAs, although mostly non-coding, are transcribed at high rates and are degraded by an unknown mechanism. Here we describe a dedicated mechanism of degradation of G4-containing RNAs, which is based on cooperation between mitochondrial degradosome and quasi-RNA recognition motif (qRRM) protein GRSF1. This cooperation prevents accumulation of G4-containing transcripts in human mitochondria. In vitro reconstitution experiments show that GRSF1 promotes G4 melting that facilitates degradosome-mediated decay. Among degradosome and GRSF1 regulated transcripts we identified one that undergoes post-transcriptional modification. We show that GRSF1 proteins form a distinct qRRM group found only in vertebrates. The appearance of GRSF1 coincided with changes in the mitochondrial genome, which allows the emergence of G4-containing RNAs. We propose that GRSF1 appearance is an evolutionary adaptation enabling control of G4 RNA. G-rich RNAs encoded in mitochondrial DNA are prone to form four-stranded structures called G-quadruplexes (G4s). Here the authors show using in vitro and in vivo approaches that GRSF1 promotes melting of G4 RNA structures in mtRNAs, thus leading to their decay by the hSuv3–PNPase complex.