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Edited by Uttiya Basu, Columbia University, and accepted by Editorial Board Member Douglas Koshland September 13, 2018 (received for review April 26, 2018)
Significance
R loops form during transcription when the mRNA hybridizes back to the template DNA forming a stable DNA–RNA hybrid. Stable R loops can block replication and transcription machineries, leading to genome instability and human diseases. We report that the human mitochondrial degradosome (mtEXO), formed by SUV3 and PNPase, plays an important role in R-loop metabolism in the mitochondria apart from preventing dsRNA accumulation, with implications in replication and preventing instability of the mitochondrial genome. Our findings help establish a connection between the RNA processing activities of the mtEXO and mitochondrial genome stability, affecting mitochondria homeostasis, cellular metabolism, and human diseases.
Abstract
R loops are nucleic acid structures comprising an DNA–RNA hybrid and a displaced single-stranded DNA. These structures may occur transiently during transcription, playing essential biological functions. However, persistent R loops may become pathological as they are important drivers of genome instability and have been associated with human diseases. The mitochondrial degradosome is a functionally conserved complex from bacteria to human mitochondria. It is composed of the ATP-dependent RNA and DNA helicase SUV3 and the PNPase ribonuclease, playing a central role in mitochondrial RNA surveillance and degradation. Here we describe a new role for the mitochondrial degradosome in preventing the accumulation of pathological R loops in the mitochondrial DNA, in addition to preventing dsRNA accumulation. Our data indicate that, similar to the molecular mechanisms acting in the nucleus, RNA surveillance mechanisms in the mitochondria are crucial to maintain its genome integrity by counteracting pathological R-loop accumulation.
Footnotes
- ↵1To whom correspondence should be addressed. Email: aguilo{at}us.es.
Author contributions: S.S. and A.A. designed research; S.S. and L.P.C. performed research; S.S. and A.A. analyzed data; and S.S. and A.A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. U.B. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1807258115/-/DCSupplemental.
Published under the PNAS license.
Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability
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