title: The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis.
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.
authors.affiliation: Human Development and Health Academic Unit, University of Southampton, Faculty of Medicine, and Complete Fertility Centre Southampton, Princess Anne Hospital, Southampton, UK.|Department of Obstetrics and Gynecology, Faculty of Medicine, University of Malaya, 59100 Kuala Lumpur, Malaysia.
authors.forename: Mukhri
authors.initials: M
authors.lastname: Hamdan
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Jones
authors.affiliation: Human Development and Health Academic Unit, University of Southampton, Faculty of Medicine, and Complete Fertility Centre Southampton, Princess Anne Hospital, Southampton, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheong
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Simon I R
authors.initials: SI
authors.lastname: Lane
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004715:Endometriosis / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015571:Follicular Fluid / Q000737:chemistry* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D064246:Mad2 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D060172:Morpholinos / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D064246:Mad2 Proteins; D060172:Morpholinos; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins