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Dinucleotide degradation by REXO2 maintains promoter specificity in mammalian mitochondria

Lookup NU author(s): Dr Thomas NichollsORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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. We here demonstrate that REXO2 is a specialised 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.


Publication metadata

Author(s): Nicholls TJ, Spåhr H, Jiang S, Siira SJ, Koolmeister C, Sharma S, Kauppila JHK, Jiang M, Kaever V, Rackham O, Chabes A, Falkenberg M, Filipovska A, Larsson NG, Gustafsson CM

Publication type: Article

Publication status: Published

Journal: Molecular Cell

Year: 2019

Volume: 76

Pages: 1-13

Print publication date: 05/12/2019

Online publication date: 03/10/2019

Acceptance date: 04/09/2019

Date deposited: 03/10/2019

ISSN (print): 1097-2765

ISSN (electronic): 1097-4164

Publisher: Cell Press

URL: https://doi.org/10.1016/j.molcel.2019.09.010

DOI: 10.1016/j.molcel.2019.09.010


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Funding

Funder referenceFunder name
2015-00418
2016-599
2017.0080
213464/Z/18/ZWellcome Trust
2016.0050
2016-816
2017-01257
2017-631
2018-02439
2018-02579
2018-602
ALFGBG-728151
683191
741366
ALFGBG-727491
M811Rosetrees Trust
SLL2018.0471

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