title: Oocytes progress beyond prophase in the presence of DNA damage.
abstract: In the female germline, DNA damage has the potential to induce infertility and even to lead to genetic abnormalities that may be propagated to the resulting embryo [1, 2]. The protracted arrest in meiotic prophase makes oocytes particularly susceptible to the accumulation of environmental insults, including DNA damage. Despite this significant potential to harm reproductive capacity, surprisingly little is known about the DNA damage response in oocytes. We show that double-strand breaks in meiotically competent G2/prophase-arrested mouse oocytes do not prevent entry into M phase, unless levels of damage are severe. This lack of an efficient DNA damage checkpoint is because oocytes fail to effectively activate the master regulator of the DNA damage response pathway, ATM (ataxia telangiectasia mutated) kinase. In addition, instead of inhibiting cyclin B-CDK1 through destruction of Cdc25A phosphatase, oocytes utilize an inhibitory phosphorylation of Cdc25B. We conclude that oocytes are the only nontransformed cells that fail to launch a robust G2 phase DNA damage checkpoint and that this renders them sensitive to genomic instability.
authors.affiliation: Department of Cell and Developmental Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK. p.marangos@ucl.ac.uk
authors.forename: Petros
authors.initials: P
authors.lastname: Marangos
authors.forename: John
authors.initials: J
authors.lastname: Carroll
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D008540:Meiosis; D051379:Mice; D009865:Oocytes / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C517005:Cdc25a protein, mouse; C517006:Cdc25b protein, mouse; D020687:cdc25 Phosphatases