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Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage

Environmental and metabolic sources of reactive oxygen species (ROS) can damage DNA, proteins and lipids to promote disease. Regulation of gene expression can prevent this damage and can include increased transcription, translation and post translational modification. Cellular responses to ROS play...

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Autores principales: Endres, Lauren, Begley, Ulrike, Clark, Ryan, Gu, Chen, Dziergowska, Agnieszka, Małkiewicz, Andrzej, Melendez, J. Andres, Dedon, Peter C., Begley, Thomas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492958/
https://www.ncbi.nlm.nih.gov/pubmed/26147969
http://dx.doi.org/10.1371/journal.pone.0131335
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author Endres, Lauren
Begley, Ulrike
Clark, Ryan
Gu, Chen
Dziergowska, Agnieszka
Małkiewicz, Andrzej
Melendez, J. Andres
Dedon, Peter C.
Begley, Thomas J.
author_facet Endres, Lauren
Begley, Ulrike
Clark, Ryan
Gu, Chen
Dziergowska, Agnieszka
Małkiewicz, Andrzej
Melendez, J. Andres
Dedon, Peter C.
Begley, Thomas J.
author_sort Endres, Lauren
collection PubMed
description Environmental and metabolic sources of reactive oxygen species (ROS) can damage DNA, proteins and lipids to promote disease. Regulation of gene expression can prevent this damage and can include increased transcription, translation and post translational modification. Cellular responses to ROS play important roles in disease prevention, with deficiencies linked to cancer, neurodegeneration and ageing. Here we detail basal and damage-induced translational regulation of a group of oxidative-stress response enzymes by the tRNA methyltransferase Alkbh8. Using a new gene targeted knockout mouse cell system, we show that Alkbh8(-/-) embryonic fibroblasts (MEFs) display elevated ROS levels, increased DNA and lipid damage and hallmarks of cellular stress. We demonstrate that Alkbh8 is induced in response to ROS and is required for the efficient expression of selenocysteine-containing ROS detoxification enzymes belonging to the glutathione peroxidase (Gpx1, Gpx3, Gpx6 and likely Gpx4) and thioredoxin reductase (TrxR1) families. We also show that, in response to oxidative stress, the tRNA modification 5-methoxycarbonylmethyl-2′-O-methyluridine (mcm(5)Um) increases in normal MEFs to drive the expression of ROS detoxification enzymes, with this damage-induced reprogramming of tRNA and stop-codon recoding corrupted in Alkbh8(-/-) MEFS. These studies define Alkbh8 and tRNA modifications as central regulators of cellular oxidative stress responses in mammalian systems. In addition they highlight a new animal model for use in environmental and cancer studies and link translational regulation to the prevention of DNA and lipid damage.
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spelling pubmed-44929582015-07-15 Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage Endres, Lauren Begley, Ulrike Clark, Ryan Gu, Chen Dziergowska, Agnieszka Małkiewicz, Andrzej Melendez, J. Andres Dedon, Peter C. Begley, Thomas J. PLoS One Research Article Environmental and metabolic sources of reactive oxygen species (ROS) can damage DNA, proteins and lipids to promote disease. Regulation of gene expression can prevent this damage and can include increased transcription, translation and post translational modification. Cellular responses to ROS play important roles in disease prevention, with deficiencies linked to cancer, neurodegeneration and ageing. Here we detail basal and damage-induced translational regulation of a group of oxidative-stress response enzymes by the tRNA methyltransferase Alkbh8. Using a new gene targeted knockout mouse cell system, we show that Alkbh8(-/-) embryonic fibroblasts (MEFs) display elevated ROS levels, increased DNA and lipid damage and hallmarks of cellular stress. We demonstrate that Alkbh8 is induced in response to ROS and is required for the efficient expression of selenocysteine-containing ROS detoxification enzymes belonging to the glutathione peroxidase (Gpx1, Gpx3, Gpx6 and likely Gpx4) and thioredoxin reductase (TrxR1) families. We also show that, in response to oxidative stress, the tRNA modification 5-methoxycarbonylmethyl-2′-O-methyluridine (mcm(5)Um) increases in normal MEFs to drive the expression of ROS detoxification enzymes, with this damage-induced reprogramming of tRNA and stop-codon recoding corrupted in Alkbh8(-/-) MEFS. These studies define Alkbh8 and tRNA modifications as central regulators of cellular oxidative stress responses in mammalian systems. In addition they highlight a new animal model for use in environmental and cancer studies and link translational regulation to the prevention of DNA and lipid damage. Public Library of Science 2015-07-06 /pmc/articles/PMC4492958/ /pubmed/26147969 http://dx.doi.org/10.1371/journal.pone.0131335 Text en © 2015 Endres et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Endres, Lauren
Begley, Ulrike
Clark, Ryan
Gu, Chen
Dziergowska, Agnieszka
Małkiewicz, Andrzej
Melendez, J. Andres
Dedon, Peter C.
Begley, Thomas J.
Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage
title Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage
title_full Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage
title_fullStr Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage
title_full_unstemmed Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage
title_short Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage
title_sort alkbh8 regulates selenocysteine-protein expression to protect against reactive oxygen species damage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492958/
https://www.ncbi.nlm.nih.gov/pubmed/26147969
http://dx.doi.org/10.1371/journal.pone.0131335
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