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Defying DNA Double-Strand Break-Induced Death during Prophase I Meiosis by Temporal TAp63α Phosphorylation Regulation in Developing Mouse Oocytes

机译:在发育中的小鼠卵母细胞中通过时间TAp63α磷酸化调控来抵御前期减数分裂中DNA双链断裂诱导的死亡。

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The dichotomy in DNA damage sensitivity of developing mouse oocytes during female germ line development is striking. Embryonic oocytes withstand hundreds of programmed DNA double-strand breaks (DSBs) required for meiotic recombination. Postnatal immature oocytes fail to tolerate even a few DSBs induced by gamma radiation treatment. TAp63α, a p53 family member, undergoes phosphorylation and mediates postnatal immature oocyte death following gamma radiation treatment, which is thought important for germ line quality maintenance. Whether prenatal meiotic oocytes tolerate DNA DSBs simply because they lack TAp63α expression is not clear. We found a significant number of oocytes in newborn mice initiate TAp63α expression and simultaneously carry meiotic DNA DSBs. However, the risk of premature death appears unlikely, because newborn oocytes strongly abate TAp63α phosphorylation induction and resist normally lethal doses of ionizing radiation damage. A calyculin A-sensitive Ser/Thr phosphatase activity downregulates TAp63α phosphorylation and ATM kinase mediates phosphorylation. Possible alterations in the relative balance of these counteracting activities during development may first temper TAp63α phosphorylation and death induction during meiotic DNA DSB repair and recombination, and afterward, implement germ line quality control in later stages. Insights into inherent DNA DSB resistance mechanisms in newborn oocytes may help prevent infertility in women in need of radiation or chemotherapy.
机译:在雌性种系发育过程中,发育中的小鼠卵母细胞对DNA损伤敏感性的二分法引人注目。胚胎卵母细胞可以承受减数分裂重组所需的数百个程序化DNA双链断裂(DSB)。产后未成熟的卵母细胞甚至不能耐受伽马放射治疗诱导的一些DSB。 TAp63α是p53家族的成员,经过γ射线处理后会发生磷酸化作用,并介导出生后未成熟的卵母细胞死亡,这对维持种系质量至关重要。尚不清楚产前减数分裂卵母细胞是否仅由于缺乏TAp63α表达而耐受DNA DSB。我们发现新生小鼠中大量卵母细胞会启动TAp63α表达并同时携带减数分裂DNA DSB。但是,过早死亡的风险似乎不太可能,因为新生卵母细胞会强烈减弱TAp63α的磷酸化诱导作用,并能抵抗正常致死剂量的电离辐射损伤。 Calyculin A敏感的Ser / Thr磷酸酶活性下调TAp63α磷酸化,而ATM激酶介导磷酸化。这些反作用活性在发育过程中相对平衡的可能改变可能会首先减缓减数分裂DNA DSB修复和重组过程中的TAp63α磷酸化和死亡诱导,然后在以后的阶段实施种系质量控制。洞察新生卵母细胞固有的DNA DSB耐药机制可能有助于预防需要放疗或化疗的女性的不育症。

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