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Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA

RNA decay is a key element of mitochondrial RNA metabolism. To date, the only well-documented machinery that plays a role in mtRNA decay in humans is the complex of polynucleotide phosphorylase (PNPase) and SUV3 helicase, forming the degradosome. REXO2, a homolog of prokaryotic oligoribonucleases pr...

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Autores principales: Szewczyk, Maciej, Malik, Deepshikha, Borowski, Lukasz S, Czarnomska, Sylwia D, Kotrys, Anna V, Klosowska-Kosicka, Kamila, Nowotny, Marcin, Szczesny, Roman J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261184/
https://www.ncbi.nlm.nih.gov/pubmed/32365187
http://dx.doi.org/10.1093/nar/gkaa302
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author Szewczyk, Maciej
Malik, Deepshikha
Borowski, Lukasz S
Czarnomska, Sylwia D
Kotrys, Anna V
Klosowska-Kosicka, Kamila
Nowotny, Marcin
Szczesny, Roman J
author_facet Szewczyk, Maciej
Malik, Deepshikha
Borowski, Lukasz S
Czarnomska, Sylwia D
Kotrys, Anna V
Klosowska-Kosicka, Kamila
Nowotny, Marcin
Szczesny, Roman J
author_sort Szewczyk, Maciej
collection PubMed
description RNA decay is a key element of mitochondrial RNA metabolism. To date, the only well-documented machinery that plays a role in mtRNA decay in humans is the complex of polynucleotide phosphorylase (PNPase) and SUV3 helicase, forming the degradosome. REXO2, a homolog of prokaryotic oligoribonucleases present in humans both in mitochondria and the cytoplasm, was earlier shown to be crucial for maintaining mitochondrial homeostasis, but its function in mitochondria has not been fully elucidated. In the present study, we created a cellular model that enables the clear dissection of mitochondrial and non-mitochondrial functions of human REXO2. We identified a novel mitochondrial short RNA, referred to as ncH2, that massively accumulated upon REXO2 silencing. ncH2 degradation occurred independently of the mitochondrial degradosome, strongly supporting the hypothesis that ncH2 is a primary substrate of REXO2. We also investigated the global impact of REXO2 depletion on mtRNA, revealing the importance of the protein for maintaining low steady-state levels of mitochondrial antisense transcripts and double-stranded RNA. Our detailed biochemical and structural studies provide evidence of sequence specificity of the REXO2 oligoribonuclease. We postulate that REXO2 plays dual roles in human mitochondria, ‘scavenging’ nanoRNAs that are produced by the degradosome and clearing short RNAs that are generated by RNA processing.
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spelling pubmed-72611842020-06-03 Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA Szewczyk, Maciej Malik, Deepshikha Borowski, Lukasz S Czarnomska, Sylwia D Kotrys, Anna V Klosowska-Kosicka, Kamila Nowotny, Marcin Szczesny, Roman J Nucleic Acids Res Molecular Biology RNA decay is a key element of mitochondrial RNA metabolism. To date, the only well-documented machinery that plays a role in mtRNA decay in humans is the complex of polynucleotide phosphorylase (PNPase) and SUV3 helicase, forming the degradosome. REXO2, a homolog of prokaryotic oligoribonucleases present in humans both in mitochondria and the cytoplasm, was earlier shown to be crucial for maintaining mitochondrial homeostasis, but its function in mitochondria has not been fully elucidated. In the present study, we created a cellular model that enables the clear dissection of mitochondrial and non-mitochondrial functions of human REXO2. We identified a novel mitochondrial short RNA, referred to as ncH2, that massively accumulated upon REXO2 silencing. ncH2 degradation occurred independently of the mitochondrial degradosome, strongly supporting the hypothesis that ncH2 is a primary substrate of REXO2. We also investigated the global impact of REXO2 depletion on mtRNA, revealing the importance of the protein for maintaining low steady-state levels of mitochondrial antisense transcripts and double-stranded RNA. Our detailed biochemical and structural studies provide evidence of sequence specificity of the REXO2 oligoribonuclease. We postulate that REXO2 plays dual roles in human mitochondria, ‘scavenging’ nanoRNAs that are produced by the degradosome and clearing short RNAs that are generated by RNA processing. Oxford University Press 2020-06-04 2020-05-04 /pmc/articles/PMC7261184/ /pubmed/32365187 http://dx.doi.org/10.1093/nar/gkaa302 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Molecular Biology
Szewczyk, Maciej
Malik, Deepshikha
Borowski, Lukasz S
Czarnomska, Sylwia D
Kotrys, Anna V
Klosowska-Kosicka, Kamila
Nowotny, Marcin
Szczesny, Roman J
Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA
title Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA
title_full Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA
title_fullStr Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA
title_full_unstemmed Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA
title_short Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA
title_sort human rexo2 controls short mitochondrial rnas generated by mtrna processing and decay machinery to prevent accumulation of double-stranded rna
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261184/
https://www.ncbi.nlm.nih.gov/pubmed/32365187
http://dx.doi.org/10.1093/nar/gkaa302
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