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• W2779832521 abstract "Department of Molecular Oncology, BSRC ‘‘AlexanderFleming,’’ Athens 16672, GreeceSummaryIn the female germline, DNA damage has the potential toinduce infertility and even to lead to genetic abnormalitiesthat may be propagated to the resulting embryo [1, 2]. Theprotracted arrest in meiotic prophase makes oocytes partic-ularly susceptible to the accumulation of environmentalinsults, including DNA damage. Despite this significantpotential to harm reproductive capacity, surprisingly littleis known about the DNA damage response in oocytes. Weshow that double-strand breaks in meiotically competentG2/prophase-arrested mouse oocytes do not prevent entryinto M phase, unless levels of damage are severe. This lackof an efficient DNA damage checkpoint is because oocytesfail to effectively activate the master regulator of the DNAdamage response pathway, ATM (ataxia telangiectasiamutated) kinase. In addition, instead of inhibiting cyclinB-CDK1 through destruction of Cdc25A phosphatase,oocytes utilize an inhibitory phosphorylation of Cdc25B.We conclude thatoocytes are the onlynontransformed cellsthat fail to launch a robust G2 phase DNA damage check-point and that this renders them sensitive to genomicinstability.Results and DiscussionMouse Oocytes Enter M Phase in the Presenceof DNA DamageIn somatic cells, at the G2 stage, DNA double-strand breakscause the autophosphorylation and subsequent activation ofthe master DNA damage checkpoint regulator, ATM (ataxiatelangiectasia mutated) kinase [3, 4]. ATM activation is theinitial step in the establishment of the G2 checkpoint followingDNA damage in the form of DNA double-strand breaks. At thesites of damage, ATM phosphorylates histone H2AX (gH2AX),which forms a platform for the recruitment of the necessarycheckpoint and repair factors [5]. The establishment of thecheckpoint requires the ATM-mediated activation of check-point kinases, Chk1 and Chk2 [6, 7]. Cell-cycle arrest at theG2 stage is a result of a Chk1/Chk2-dependent degradationof the Cdc25A phosphatase [8–10], but in some cases theinhibitory phosphorylation of Cdc25B or Cdc25C [11, 12],leading to a failure to activate cyclin B-CDK1 [9–11].The few studies that have been undertaken in fully grownoocytes hint at the possibility of a limited DNA damageresponse [13, 14]. To investigate the DNA damage checkpointinoocytes,weinitiallytestedtheabilityofetoposide,atopoiso-merase II inhibitor, to cause double-strand breaks as it doesin somatic cells [15]. The data verified that treatment withetoposide(5mg/mlfor3hr)causesDNAdamageasevidencedby the presence of phosphorylated H2AX at Ser139 (gH2AX)[16](Figure 1A). Having identified that DNA damage can bedetected at this concentration, we examined the ability ofoocytestoprogressintoMphaseofmeiosisIaftera3hrexpo-sure to increasing concentrations (5–100 mg/ml) of etoposide.Despite the presence of DNA damage at the lower concentra-tions tested, oocytes were capable of undergoing germinalvesicle breakdown (GVBD) and entering M phase at nearnormal kinetics (Figure 1B). Etoposide-treated oocytes thatundergo GVBD still show a 6-fold greater gH2AX stainingintensity compared to controls (see Figures S1A and S1Bavailable online). Thus, the absence of cell-cycle arrest in thepresence of DNA damage is likely to be the result of an inade-quate DNA damage checkpoint rather than highly efficientDNA repair mechanisms. As the etoposide concentrationsincreased,therateandtheabilitytoundergoGVBDweregrad-ually reduced (Figure 1B). In order to achieve an effectiveG2/prophase arrest, etoposide concentrations at the upperendofthedoseresponse(50–100mg/ml,3hr)werenecessary;inducinggreaterthan80%ofoocytestoremainarrestedattheG2/prophase stage after 5 hr of culture (Figure 1B).The ability to enter M phase in the presence of DNAdamage increases with prolonged culture (Figure 1C). Evenat 100 mg/ml where only approximately 20% of oocytes hadundergone GVBD after 5 hr, this increased to over 60% after20 hr. This recovery from checkpoint arrest was apparentlynot due to DNA repair because gH2AX staining was presentin oocytes that had undergone GVBD (Figures S1C and S1D).Morelikely,theincreaseinGVBDmaybeattributedto‘‘check-point adaptation,’’ a mechanism seen in somatic cells thatcausestheinactivationoftheG2checkpointdespiteextensiveand irreversible DNA damage [17].High Levels of Exposure to Etoposide Activatean ATM/Chk1-Dependent DNA Damage CheckpointHaving found that oocytes appear not to launch a powerfulDNA damage checkpoint, we next sought to define the pres-ence of the major players in the response to DNA damage,namely ATM and Chk1. In this series of experiments, oocyteswere exposed to etoposide as for the previous experimentand labeled with antibodies to detect gH2AX and active ATMas determined by monitoring the autophosphorylation ofATM at Ser1981 (ATM-P) [3](Figures 2A–2C). Exposure toincreasing concentrations of etoposide caused an increasein gH2AX as well as ATM activation (Figures 2A and 2B). Bycorrelating the fluorescence staining in Figure 2A with theG2/prophase arrest datafrom Figure 1B at different etoposideconcentrations, we confirmed a positive relationship betweenATM/gH2AX and G2 arrest (Figure 2C).ThecorrelationbetweenATMstainingandtheoccurrenceofG2/prophase arrest suggests that ATM is involved in oocytecheckpoint activation. To test the specificity of the proposed" @default.
• W2779832521 created "2018-01-05" @default.
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• W2779832521 date "2012-01-01" @default.
• W2779832521 modified "2023-09-27" @default.
• W2779832521 title "Report Oocytes Progress beyond Prophase in the Presence of DNA Damage" @default.
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