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

• Published in: Scientific reports Vol. 6; no. 1; p. 36994
• Main Authors: Hamdan, Mukhri, Jones, Keith T., Cheong, Ying, Lane, Simon I. R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.11.2016; Nature Publishing Group
• Subjects: 14/19; 14/34; 14/63; 631/443/494/2732/1577; 631/80/304; 631/80/641/1633; 631/80/641/2187; 631/80/86/2371; 64/60; Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Cycle Checkpoints - drug effects; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Endometriosis; Endometriosis - metabolism; Endometriosis - pathology; Female; Fertility; Follicular fluid; Follicular Fluid - chemistry; Follicular Fluid - metabolism; Free Radical Scavengers - pharmacology; Humanities and Social Sciences; Humans; Hydrogen Peroxide - toxicity; Mad2 Proteins - antagonists & inhibitors; Mad2 Proteins - genetics; Mad2 Proteins - metabolism; Meiosis; Metaphase; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Morpholinos - metabolism; multidisciplinary; Oocytes; Oocytes - cytology; Oocytes - growth & development; Oocytes - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Spindle Apparatus - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep36994

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.