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Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1
Hypoxia-induced replication stress is one of the most physiologically relevant signals known to activate ATM in tumors. Recently, the ATM interactor (ATMIN) was identified as critical for replication stress-induced activation of ATM in response to aphidicolin and hydroxyurea. This suggests an essent...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753685/ https://www.ncbi.nlm.nih.gov/pubmed/26875667 http://dx.doi.org/10.1038/srep21698 |
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author | Leszczynska, Katarzyna B. Göttgens, Eva-Leonne Biasoli, Deborah Olcina, Monica M. Ient, Jonathan Anbalagan, Selvakumar Bernhardt, Stephan Giaccia, Amato J. Hammond, Ester M. |
author_facet | Leszczynska, Katarzyna B. Göttgens, Eva-Leonne Biasoli, Deborah Olcina, Monica M. Ient, Jonathan Anbalagan, Selvakumar Bernhardt, Stephan Giaccia, Amato J. Hammond, Ester M. |
author_sort | Leszczynska, Katarzyna B. |
collection | PubMed |
description | Hypoxia-induced replication stress is one of the most physiologically relevant signals known to activate ATM in tumors. Recently, the ATM interactor (ATMIN) was identified as critical for replication stress-induced activation of ATM in response to aphidicolin and hydroxyurea. This suggests an essential role for ATMIN in ATM regulation during hypoxia, which induces replication stress. However, ATMIN also has a role in base excision repair, a process that has been demonstrated to be repressed and less efficient in hypoxic conditions. Here, we demonstrate that ATMIN is dispensable for ATM activation in hypoxia and in contrast to ATM, does not affect cell survival and radiosensitivity in hypoxia. Instead, we show that in hypoxic conditions ATMIN expression is repressed. Repression of ATMIN in hypoxia is mediated by both p53 and HIF-1α in an oxygen dependent manner. The biological consequence of ATMIN repression in hypoxia is decreased expression of the target gene, DYNLL1. An expression signature associated with p53 activity was negatively correlated with DYNLL1 expression in patient samples further supporting the p53 dependent repression of DYNLL1. Together, these data demonstrate multiple mechanisms of ATMIN repression in hypoxia with consequences including impaired BER and down regulation of the ATMIN transcriptional target, DYNLL1. |
format | Online Article Text |
id | pubmed-4753685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47536852016-02-23 Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 Leszczynska, Katarzyna B. Göttgens, Eva-Leonne Biasoli, Deborah Olcina, Monica M. Ient, Jonathan Anbalagan, Selvakumar Bernhardt, Stephan Giaccia, Amato J. Hammond, Ester M. Sci Rep Article Hypoxia-induced replication stress is one of the most physiologically relevant signals known to activate ATM in tumors. Recently, the ATM interactor (ATMIN) was identified as critical for replication stress-induced activation of ATM in response to aphidicolin and hydroxyurea. This suggests an essential role for ATMIN in ATM regulation during hypoxia, which induces replication stress. However, ATMIN also has a role in base excision repair, a process that has been demonstrated to be repressed and less efficient in hypoxic conditions. Here, we demonstrate that ATMIN is dispensable for ATM activation in hypoxia and in contrast to ATM, does not affect cell survival and radiosensitivity in hypoxia. Instead, we show that in hypoxic conditions ATMIN expression is repressed. Repression of ATMIN in hypoxia is mediated by both p53 and HIF-1α in an oxygen dependent manner. The biological consequence of ATMIN repression in hypoxia is decreased expression of the target gene, DYNLL1. An expression signature associated with p53 activity was negatively correlated with DYNLL1 expression in patient samples further supporting the p53 dependent repression of DYNLL1. Together, these data demonstrate multiple mechanisms of ATMIN repression in hypoxia with consequences including impaired BER and down regulation of the ATMIN transcriptional target, DYNLL1. Nature Publishing Group 2016-02-15 /pmc/articles/PMC4753685/ /pubmed/26875667 http://dx.doi.org/10.1038/srep21698 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Leszczynska, Katarzyna B. Göttgens, Eva-Leonne Biasoli, Deborah Olcina, Monica M. Ient, Jonathan Anbalagan, Selvakumar Bernhardt, Stephan Giaccia, Amato J. Hammond, Ester M. Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 |
title | Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 |
title_full | Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 |
title_fullStr | Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 |
title_full_unstemmed | Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 |
title_short | Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1 |
title_sort | mechanisms and consequences of atmin repression in hypoxic conditions: roles for p53 and hif-1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753685/ https://www.ncbi.nlm.nih.gov/pubmed/26875667 http://dx.doi.org/10.1038/srep21698 |
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