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Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication
Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mam...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405111/ https://www.ncbi.nlm.nih.gov/pubmed/28416140 http://dx.doi.org/10.1016/j.molcel.2017.03.005 |
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author | Foskolou, Iosifina P. Jorgensen, Christian Leszczynska, Katarzyna B. Olcina, Monica M. Tarhonskaya, Hanna Haisma, Bauke D’Angiolella, Vincenzo Myers, William K. Domene, Carmen Flashman, Emily Hammond, Ester M. |
author_facet | Foskolou, Iosifina P. Jorgensen, Christian Leszczynska, Katarzyna B. Olcina, Monica M. Tarhonskaya, Hanna Haisma, Bauke D’Angiolella, Vincenzo Myers, William K. Domene, Carmen Flashman, Emily Hammond, Ester M. |
author_sort | Foskolou, Iosifina P. |
collection | PubMed |
description | Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and identified responsible residues in RRM2B. The importance of RRM2B in the response to tumor hypoxia is further illustrated by correlation of its expression with a hypoxic signature in patient samples and its roles in tumor growth and radioresistance. Our data provide mechanistic insight into RNR biology, highlighting RRM2B as a hypoxic-specific, anti-cancer therapeutic target. |
format | Online Article Text |
id | pubmed-5405111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54051112017-05-05 Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication Foskolou, Iosifina P. Jorgensen, Christian Leszczynska, Katarzyna B. Olcina, Monica M. Tarhonskaya, Hanna Haisma, Bauke D’Angiolella, Vincenzo Myers, William K. Domene, Carmen Flashman, Emily Hammond, Ester M. Mol Cell Article Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and identified responsible residues in RRM2B. The importance of RRM2B in the response to tumor hypoxia is further illustrated by correlation of its expression with a hypoxic signature in patient samples and its roles in tumor growth and radioresistance. Our data provide mechanistic insight into RNR biology, highlighting RRM2B as a hypoxic-specific, anti-cancer therapeutic target. Cell Press 2017-04-20 /pmc/articles/PMC5405111/ /pubmed/28416140 http://dx.doi.org/10.1016/j.molcel.2017.03.005 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Foskolou, Iosifina P. Jorgensen, Christian Leszczynska, Katarzyna B. Olcina, Monica M. Tarhonskaya, Hanna Haisma, Bauke D’Angiolella, Vincenzo Myers, William K. Domene, Carmen Flashman, Emily Hammond, Ester M. Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication |
title | Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication |
title_full | Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication |
title_fullStr | Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication |
title_full_unstemmed | Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication |
title_short | Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication |
title_sort | ribonucleotide reductase requires subunit switching in hypoxia to maintain dna replication |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405111/ https://www.ncbi.nlm.nih.gov/pubmed/28416140 http://dx.doi.org/10.1016/j.molcel.2017.03.005 |
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