Huang Xingxu, Andreu-Vieyra Claudia V, Wang Meizhi, Cooney Austin J, Matzuk Martin M, Zhang Pumin
Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China.
Mol Cell Biol. 2009 Mar;29(6):1498-505. doi: 10.1128/MCB.01778-08. Epub 2009 Jan 5.
Separase is a critical protease that catalyzes the cleavage of sister chromatid cohesins to allow the separation of sister chromatids in the anaphase. Its activity must be inhibited prior to the onset of the anaphase. Two inhibitory mechanisms exist in vertebrates that block the protease activity. One mechanism is through binding and inhibition by securin, and another is phosphorylation on Ser1126 (in humans [Ser1121 in mice]). These two mechanisms are largely redundant. However, phosphorylation on Ser1121 is critical for the prevention of premature sister separation in embryonic germ cells. As a result, Ser1121-to-Ala mutation leads to depletion of germ cells in development and subsequently to infertility in mice. Here, we report that the same mutation also causes embryogenesis failure between the 8- and 16-cell stages in mice. Our results indicate a critical role of separase phosphorylation in germ cell development as well as in early embryogenesis. Thus, deregulation of separase may be a significant contributor to infertility in humans.
分离酶是一种关键的蛋白酶，它催化姐妹染色单体黏连蛋白的裂解，以使姐妹染色单体在后期能够分离。在后期开始之前，其活性必须受到抑制。脊椎动物中存在两种抑制机制来阻断蛋白酶活性。一种机制是通过securin的结合和抑制，另一种是Ser1126（人类中为Ser1121，小鼠中为Ser1121）位点的磷酸化。这两种机制在很大程度上是冗余的。然而，Ser1121位点的磷酸化对于防止胚胎生殖细胞中姐妹染色单体过早分离至关重要。因此，Ser1121突变为丙氨酸会导致发育过程中生殖细胞的耗竭，进而导致小鼠不育。在此，我们报告相同的突变也会导致小鼠在8细胞期至16细胞期之间胚胎发育失败。我们的结果表明分离酶磷酸化在生殖细胞发育以及早期胚胎发生中起着关键作用。因此，分离酶的失调可能是导致人类不育的一个重要因素。
