p63 protects the female germ line during meiotic arrest
p63 protects the female germ line during meiotic arrest
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DOI：
10.1038/nature05337
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发表时间：
2006-11-30
期刊：
影响因子：
64.8
通讯作者：
McKeon, Frank
中科院分区：
文献类型：
--
作者：
Suh, Eun-Kyung;Yang, Annie;McKeon, Frank
哺乳动物雌性种系减数分裂的特点是减数分裂 I 前期在同源染色体重组和排卵之间的长期停滞 (1)。人们对如何在这些停滞的卵母细胞中检测到 DNA 损伤知之甚少，但人们普遍认为它与 p53（哺乳动物的一种重要肿瘤抑制因子）有关(2-4)。虽然 p53 在监测体细胞基因组方面的功能很清楚，但关于 p53 对种系完整性的重要性尚未达成共识。在这里，我们表明，p53 同源物 p63（参考文献 5、6），特别是 TAp63 亚型，在减数分裂停滞期间在雌性生殖细胞中组成型表达，并且在不涉及 p53 的 DNA 损伤诱导的卵母细胞死亡过程中至关重要。我们还表明，DNA 损伤会诱导 p63 磷酸化及其与 p53 同源 DNA 位点的结合，并且这些事件与卵母细胞死亡有关。我们的数据支持这样一个模型，即p63是p53家族的原始成员，并在监测雌性生殖系完整性的保守过程中发挥作用，而p53的功能仅限于脊椎动物体细胞抑制肿瘤。这些发现对于理解女性生殖系保真度、生育力调节和肿瘤抑制机制的进化具有重要意义。
Meiosis in the female germ line of mammals is distinguished by a prolonged arrest in prophase of meiosis I between homologous chromosome recombination and ovulation(1). How DNA damage is detected in these arrested oocytes is poorly understood, but it is variably thought to involve p53, a central tumour suppressor in mammals(2-4). While the function of p53 in monitoring the genome of somatic cells is clear, a consensus for the importance of p53 for germ line integrity has yet to emerge. Here we show that the p53 homologue p63 (refs 5, 6), and specifically the TAp63 isoform, is constitutively expressed in female germ cells during meiotic arrest and is essential in a process of DNA damage-induced oocyte death not involving p53. We also show that DNA damage induces both the phosphorylation of p63 and its binding to p53 cognate DNA sites and that these events are linked to oocyte death. Our data support a model whereby p63 is the primordial member of the p53 family and acts in a conserved process of monitoring the integrity of the female germ line, whereas the functions of p53 are restricted to vertebrate somatic cells for tumour suppression. These findings have implications for understanding female germ line fidelity, the regulation of fertility and the evolution of tumour suppressor mechanisms.