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Structural insights into nanoRNA degradation by human Rexo2

Human RNA exoribonuclease 2 (Rexo2) is an evolutionarily conserved 3′-to-5′ DEDDh-family exonuclease located primarily in mitochondria. Rexo2 degrades small RNA oligonucleotides of <5 nucleotides (nanoRNA) in a way similar to Escherichia coli Oligoribonuclease (ORN), suggesting that it plays a ro...

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Autores principales: Chu, Lee-Ya, Agrawal, Sashank, Chen, Yi-Ping, Yang, Wei-Zen, Yuan, Hanna S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521605/
https://www.ncbi.nlm.nih.gov/pubmed/30926754
http://dx.doi.org/10.1261/rna.070557.119
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author Chu, Lee-Ya
Agrawal, Sashank
Chen, Yi-Ping
Yang, Wei-Zen
Yuan, Hanna S.
author_facet Chu, Lee-Ya
Agrawal, Sashank
Chen, Yi-Ping
Yang, Wei-Zen
Yuan, Hanna S.
author_sort Chu, Lee-Ya
collection PubMed
description Human RNA exoribonuclease 2 (Rexo2) is an evolutionarily conserved 3′-to-5′ DEDDh-family exonuclease located primarily in mitochondria. Rexo2 degrades small RNA oligonucleotides of <5 nucleotides (nanoRNA) in a way similar to Escherichia coli Oligoribonuclease (ORN), suggesting that it plays a role in RNA turnover in mitochondria. However, how Rexo2 preferentially binds and degrades nanoRNA remains elusive. Here, we show that Rexo2 binds small RNA and DNA oligonucleotides with the highest affinity, and it is most robust in degrading small nanoRNA into mononucleotides in the presence of magnesium ions. We further determined three crystal structures of Rexo2 in complex with single-stranded RNA or DNA at resolutions of 1.8–2.2 Å. Rexo2 forms a homodimer and interacts mainly with the last two 3′-end nucleobases of substrates by hydrophobic and π−π stacking interactions via Leu53, Trp96, and Tyr164, signifying its preference in binding and degrading short oligonucleotides without sequence specificity. Crystal structure of Rexo2 is highly similar to that of the RNA-degrading enzyme ORN, revealing a two-magnesium-ion-dependent hydrolysis mechanism. This study thus provides the molecular basis for human Rexo2, showing how it binds and degrades nanoRNA into nucleoside monophosphates and plays a crucial role in RNA salvage pathways in mammalian mitochondria.
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spelling pubmed-65216052019-06-06 Structural insights into nanoRNA degradation by human Rexo2 Chu, Lee-Ya Agrawal, Sashank Chen, Yi-Ping Yang, Wei-Zen Yuan, Hanna S. RNA Article Human RNA exoribonuclease 2 (Rexo2) is an evolutionarily conserved 3′-to-5′ DEDDh-family exonuclease located primarily in mitochondria. Rexo2 degrades small RNA oligonucleotides of <5 nucleotides (nanoRNA) in a way similar to Escherichia coli Oligoribonuclease (ORN), suggesting that it plays a role in RNA turnover in mitochondria. However, how Rexo2 preferentially binds and degrades nanoRNA remains elusive. Here, we show that Rexo2 binds small RNA and DNA oligonucleotides with the highest affinity, and it is most robust in degrading small nanoRNA into mononucleotides in the presence of magnesium ions. We further determined three crystal structures of Rexo2 in complex with single-stranded RNA or DNA at resolutions of 1.8–2.2 Å. Rexo2 forms a homodimer and interacts mainly with the last two 3′-end nucleobases of substrates by hydrophobic and π−π stacking interactions via Leu53, Trp96, and Tyr164, signifying its preference in binding and degrading short oligonucleotides without sequence specificity. Crystal structure of Rexo2 is highly similar to that of the RNA-degrading enzyme ORN, revealing a two-magnesium-ion-dependent hydrolysis mechanism. This study thus provides the molecular basis for human Rexo2, showing how it binds and degrades nanoRNA into nucleoside monophosphates and plays a crucial role in RNA salvage pathways in mammalian mitochondria. Cold Spring Harbor Laboratory Press 2019-06 /pmc/articles/PMC6521605/ /pubmed/30926754 http://dx.doi.org/10.1261/rna.070557.119 Text en © 2019 Chu et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by/4.0/ This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chu, Lee-Ya
Agrawal, Sashank
Chen, Yi-Ping
Yang, Wei-Zen
Yuan, Hanna S.
Structural insights into nanoRNA degradation by human Rexo2
title Structural insights into nanoRNA degradation by human Rexo2
title_full Structural insights into nanoRNA degradation by human Rexo2
title_fullStr Structural insights into nanoRNA degradation by human Rexo2
title_full_unstemmed Structural insights into nanoRNA degradation by human Rexo2
title_short Structural insights into nanoRNA degradation by human Rexo2
title_sort structural insights into nanorna degradation by human rexo2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521605/
https://www.ncbi.nlm.nih.gov/pubmed/30926754
http://dx.doi.org/10.1261/rna.070557.119
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