Dinucleotide Degradation by REXO2 Maintains Promoter Specificity in Mammalian Mitochondria

Mol Cell. 2019 Dec 5;76(5):784-796.e6. doi: 10.1016/j.molcel.2019.09.010.

Thomas J Nicholls ¹, Henrik Spåhr ², Shan Jiang ³, Stefan J Siira ⁴, Camilla Koolmeister ³, Sushma Sharma ⁵, Johanna H K Kauppila ⁶, Min Jiang ⁶, Volkhard Kaever ⁷, Oliver Rackham ⁸, Andrei Chabes ⁵, Maria Falkenberg ¹, Aleksandra Filipovska ⁹, Nils-Göran Larsson ¹⁰, Claes M Gustafsson ¹¹

Affiliations

1 Department of Medical Biochemistry and Cell Biology, University of Gothenburg, PO Box 440, Gothenburg 405 30, Sweden.
2 Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm 17177, Sweden.
3 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm 17177, Sweden.
4 Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia.
5 Department of Medical Biochemistry and Biophysics, Umeå University, Umeå 901 87, Sweden.
6 Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
7 Research Core Unit Metabolomics, Hannover Medical School, 30625 Hannover, Germany.
8 Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, WA 6102, Australia; Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia.
9 Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; School of Molecular Sciences, The University of Western Australia, Nedlands, WA, Australia.
10 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address: [email protected].
11 Department of Medical Biochemistry and Cell Biology, University of Gothenburg, PO Box 440, Gothenburg 405 30, Sweden. Electronic address: [email protected].

PMID: 31588022 DOI: 10.1016/j.molcel.2019.09.010

Abstract

Oligoribonucleases are conserved enzymes that degrade short RNA molecules of up to 5 nt in length and are assumed to constitute the final stage of RNA turnover. Here we demonstrate that REXO2 is a specialized dinucleotide-degrading Enzyme that shows no preference between RNA and DNA dinucleotide substrates. A heart- and skeletal-muscle-specific knockout mouse displays elevated dinucleotide levels and alterations in gene expression patterns indicative of aberrant dinucleotide-primed transcription initiation. We find that dinucleotides act as potent stimulators of mitochondrial transcription initiation in vitro. Our data demonstrate that increased levels of dinucleotides can be used to initiate transcription, leading to an increase in transcription levels from both mitochondrial promoters and other, nonspecific sequence elements in mitochondrial DNA. Efficient RNA turnover by REXO2 is thus required to maintain promoter specificity and proper regulation of transcription in mammalian mitochondria.

Keywords

POLRMT; REXO2; RNA turnover; degradosome; mitochondria; mtDNA; oligoribonuclease; transcription.

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