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

The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis
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 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.
1-8
Hamdan, Mukhri
f2846fbc-f58b-423d-af08-dc21c37dc9f0
Jones, Keith
73e8e2b5-cd67-4691-b1a9-4e7bc9066af4
Cheong, Ying
4efbba2a-3036-4dce-82f1-8b4017952c83
Lane, Simon
8e80111f-5012-4950-a228-dfb8fb9df52d
Hamdan, Mukhri
f2846fbc-f58b-423d-af08-dc21c37dc9f0
Jones, Keith
73e8e2b5-cd67-4691-b1a9-4e7bc9066af4
Cheong, Ying
4efbba2a-3036-4dce-82f1-8b4017952c83
Lane, Simon
8e80111f-5012-4950-a228-dfb8fb9df52d

Hamdan, Mukhri, Jones, Keith, Cheong, Ying and Lane, Simon (2016) The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis. Scientific Reports, 6 (36994), 1-8. (doi:10.1038/srep36994). (PMID:27841311)

Record type: Article

Abstract

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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More information

Accepted/In Press date: 20 October 2016
e-pub ahead of print date: 14 November 2016
Published date: 14 November 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 402383
URI: http://eprints.soton.ac.uk/id/eprint/402383
PURE UUID: 952342b4-5902-4e1a-b9f0-84caf029cbff
ORCID for Keith Jones: ORCID iD orcid.org/0000-0002-0294-0851
ORCID for Ying Cheong: ORCID iD orcid.org/0000-0001-7687-4597
ORCID for Simon Lane: ORCID iD orcid.org/0000-0002-8155-0981

Catalogue record

Date deposited: 15 Nov 2016 17:03
Last modified: 07 Oct 2020 02:03

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