Huang Xingxu, Andreu-Vieyra Claudia V, York J Philippe, Hatcher Rashieda, Lu Tao, Matzuk Martin M, Zhang Pumin
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Biol. 2008 Jan;6(1):e15. doi: 10.1371/journal.pbio.0060015.
Activity of separase, a cysteine protease that cleaves sister chromatid cohesin at the onset of anaphase, is tightly regulated to ensure faithful chromosome segregation and genome stability. Two mechanisms negatively regulate separase: inhibition by securin and phosphorylation on serine 1121. To gauge the physiological significance of the inhibitory phosphorylation, we created a mouse strain in which Ser1121 was mutated to Ala (S1121A). Here we report that this S1121A point mutation causes infertility in mice. We show that germ cells in the mutants are depleted during development. We further demonstrate that S1121A causes chromosome misalignment during proliferation of the postmigratory primordial germ cells, resulting in mitotic arrest, aneuploidy, and eventual cell death. Our results indicate that inhibitory phosphorylation of separase plays a critical role in the maintenance of sister chromatid cohesion and genome stability in proliferating postmigratory primordial germ cells.
Separase是一种半胱氨酸蛋白酶，在后期开始时切割姐妹染色单体黏连蛋白，其活性受到严格调控，以确保染色体忠实分离和基因组稳定性。有两种机制对Separase进行负调控：securin抑制和丝氨酸1121位点的磷酸化。为了评估抑制性磷酸化的生理意义，我们构建了一种小鼠品系，其中丝氨酸1121突变为丙氨酸（S1121A）。在此我们报告，这种S1121A点突变导致小鼠不育。我们发现突变体中的生殖细胞在发育过程中耗竭。我们进一步证明，S1121A在迁移后原始生殖细胞增殖过程中导致染色体排列错误，从而导致有丝分裂停滞、非整倍体形成及最终细胞死亡。我们的结果表明，Separase的抑制性磷酸化在维持迁移后原始生殖细胞增殖过程中的姐妹染色单体黏连和基因组稳定性方面起着关键作用。
