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The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis

Mouse oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experience...

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Autores principales: Hamdan, Mukhri, Jones, Keith T., Cheong, Ying, Lane, Simon I. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107963/
https://www.ncbi.nlm.nih.gov/pubmed/27841311
http://dx.doi.org/10.1038/srep36994
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author Hamdan, Mukhri
Jones, Keith T.
Cheong, Ying
Lane, Simon I. R.
author_facet Hamdan, Mukhri
Jones, Keith T.
Cheong, Ying
Lane, Simon I. R.
author_sort Hamdan, Mukhri
collection PubMed
description Mouse oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experienced physiologically. Here, using follicular fluid from patients with the disease endometriosis, which affects 10% of women and is associated with reduced fertility, we find raised levels of Reactive Oxygen Species (ROS), which generate DNA damage and turn on the DDR-SAC pathway. Only follicular fluid from patients with endometriosis, and not controls, produced ROS and damaged DNA in the oocyte. This activated ATM kinase, leading to SAC mediated metaphase I arrest. Completion of meiosis I could be restored by ROS scavengers, showing this is the primary trigger for arrest and offering a novel clinical therapeutic treatment. This study establishes a clinical relevance to the DDR induced SAC in oocytes. It helps explain how oocytes respond to a highly prevalent human disease and the reduced fertility associated with endometriosis.
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spelling pubmed-51079632016-11-22 The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis Hamdan, Mukhri Jones, Keith T. Cheong, Ying Lane, Simon I. R. Sci Rep Article Mouse oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experienced physiologically. Here, using follicular fluid from patients with the disease endometriosis, which affects 10% of women and is associated with reduced fertility, we find raised levels of Reactive Oxygen Species (ROS), which generate DNA damage and turn on the DDR-SAC pathway. Only follicular fluid from patients with endometriosis, and not controls, produced ROS and damaged DNA in the oocyte. This activated ATM kinase, leading to SAC mediated metaphase I arrest. Completion of meiosis I could be restored by ROS scavengers, showing this is the primary trigger for arrest and offering a novel clinical therapeutic treatment. This study establishes a clinical relevance to the DDR induced SAC in oocytes. It helps explain how oocytes respond to a highly prevalent human disease and the reduced fertility associated with endometriosis. Nature Publishing Group 2016-11-14 /pmc/articles/PMC5107963/ /pubmed/27841311 http://dx.doi.org/10.1038/srep36994 Text en Copyright © 2016, The Author(s) 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
Hamdan, Mukhri
Jones, Keith T.
Cheong, Ying
Lane, Simon I. R.
The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
title The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
title_full The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
title_fullStr The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
title_full_unstemmed The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
title_short The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
title_sort sensitivity of the dna damage checkpoint prevents oocyte maturation in endometriosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107963/
https://www.ncbi.nlm.nih.gov/pubmed/27841311
http://dx.doi.org/10.1038/srep36994
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