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PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase

Telomerase counteracts telomere shortening and cellular senescence in germ, stem, and cancer cells by adding repetitive DNA sequences to the ends of chromosomes. Telomeres are susceptible to damage by reactive oxygen species (ROS), but the consequences of oxidation of telomeres on telomere length an...

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Autores principales: Ahmed, Wareed, Lingner, Joachim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004070/
https://www.ncbi.nlm.nih.gov/pubmed/29773556
http://dx.doi.org/10.1101/gad.313460.118
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author Ahmed, Wareed
Lingner, Joachim
author_facet Ahmed, Wareed
Lingner, Joachim
author_sort Ahmed, Wareed
collection PubMed
description Telomerase counteracts telomere shortening and cellular senescence in germ, stem, and cancer cells by adding repetitive DNA sequences to the ends of chromosomes. Telomeres are susceptible to damage by reactive oxygen species (ROS), but the consequences of oxidation of telomeres on telomere length and the mechanisms that protect from ROS-mediated telomere damage are not well understood. In particular, 8-oxoguanine nucleotides at 3′ ends of telomeric substrates inhibit telomerase in vitro, whereas, at internal positions, they suppress G-quadruplex formation and were therefore proposed to promote telomerase activity. Here, we disrupt the peroxiredoxin 1 (PRDX1) and 7,8-dihydro-8-oxoguanine triphosphatase (MTH1) genes in cancer cells and demonstrate that PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 leads to ROS concentration-dependent continuous shortening of telomeres, which is due to efficient inhibition of telomere extension by telomerase. Our results identify antioxidant systems that are required to protect telomeres from oxidation and are necessary to allow telomere maintenance by telomerase conferring immortality to cancer cells.
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spelling pubmed-60040702018-11-01 PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase Ahmed, Wareed Lingner, Joachim Genes Dev Research Paper Telomerase counteracts telomere shortening and cellular senescence in germ, stem, and cancer cells by adding repetitive DNA sequences to the ends of chromosomes. Telomeres are susceptible to damage by reactive oxygen species (ROS), but the consequences of oxidation of telomeres on telomere length and the mechanisms that protect from ROS-mediated telomere damage are not well understood. In particular, 8-oxoguanine nucleotides at 3′ ends of telomeric substrates inhibit telomerase in vitro, whereas, at internal positions, they suppress G-quadruplex formation and were therefore proposed to promote telomerase activity. Here, we disrupt the peroxiredoxin 1 (PRDX1) and 7,8-dihydro-8-oxoguanine triphosphatase (MTH1) genes in cancer cells and demonstrate that PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 leads to ROS concentration-dependent continuous shortening of telomeres, which is due to efficient inhibition of telomere extension by telomerase. Our results identify antioxidant systems that are required to protect telomeres from oxidation and are necessary to allow telomere maintenance by telomerase conferring immortality to cancer cells. Cold Spring Harbor Laboratory Press 2018-05-01 /pmc/articles/PMC6004070/ /pubmed/29773556 http://dx.doi.org/10.1101/gad.313460.118 Text en © 2018 Ahmed and Lingner; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Ahmed, Wareed
Lingner, Joachim
PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase
title PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase
title_full PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase
title_fullStr PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase
title_full_unstemmed PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase
title_short PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase
title_sort prdx1 and mth1 cooperate to prevent ros-mediated inhibition of telomerase
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004070/
https://www.ncbi.nlm.nih.gov/pubmed/29773556
http://dx.doi.org/10.1101/gad.313460.118
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