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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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2018
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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. |
format | Online Article Text |
id | pubmed-6004070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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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