Vogt E, Kirsch-Volders M, Parry J, Eichenlaub-Ritter U
University of Bielefeld, Faculty of Biology, Gene Technology/Microbiology, Bielefeld, Germany.
Mutat Res. 2008 Mar 12;651(1-2):14-29. doi: 10.1016/j.mrgentox.2007.10.015. Epub 2007 Nov 9.
The spindle assembly checkpoint (SAC) monitors attachment to microtubules and tension on chromosomes in mitosis and meiosis. It represents a surveillance mechanism that halts cells in M-phase in the presence of unattached chromosomes, associated with accumulation of checkpoint components, in particular, Mad2, at the kinetochores. A complex between the anaphase promoting factor/cylosome (APC/C), its accessory protein Cdc20 and proteins of the SAC renders APC/C inactive, usually until all chromosomes are properly assembled at the spindle equator (chromosome congression) and under tension from spindle fibres. Upon release from the SAC the APC/C can target proteins like cyclin B and securin for degradation by the proteasome. Securin degradation causes activation of separase proteolytic enzyme, and in mitosis cleavage of cohesin proteins at the centromeres and arms of sister chromatids. In meiosis I only the cohesin proteins at the sister chromatid arms are cleaved. This requires meiosis specific components and tight regulation by kinase and phosphatase activities. There is no S-phase between meiotic divisions. Second meiosis resembles mitosis. Mammalian oocytes arrest constitutively at metaphase II in presence of aligned chromosomes, which is due to the activity of the cytostatic factor (CSF). The SAC has been identified in spermatogenesis and oogenesis, but gender-differences may contribute to sex-specific differential responses to aneugens. The age-related reduction in expression of components of the SAC in mammalian oocytes may act synergistically with spindle and other cell organelles' dysfunction, and a partial loss of cohesion between sister chromatids to predispose oocytes to errors in chromosome segregation. This might affect dose-response to aneugens. In view of the tendency to have children at advanced maternal ages it appears relevant to pursue studies on consequences of ageing on the susceptibility of human oocytes to the induction of meiotic error by aneugens and establish models to assess risks to human health by environmental exposures.
纺锤体组装检查点（SAC）在有丝分裂和减数分裂过程中监测染色体与微管的附着以及染色体上的张力。它代表一种监测机制，在存在未附着染色体的情况下使细胞停滞在M期，这与检查点成分，特别是Mad2在动粒处的积累有关。后期促进因子/细胞周期体（APC/C）、其辅助蛋白Cdc20和SAC的蛋白质之间形成的复合物使APC/C失活，通常直到所有染色体正确组装在纺锤体赤道（染色体排列）并受到纺锤体纤维的张力作用。从SAC释放后，APC/C可以靶向细胞周期蛋白B和securin等蛋白质，使其被蛋白酶体降解。Securin降解导致分离酶蛋白酶的激活，在有丝分裂中，着丝粒和姐妹染色单体臂上的黏连蛋白被切割。在减数分裂I中，仅姐妹染色单体臂上的黏连蛋白被切割。这需要减数分裂特异性成分以及激酶和磷酸酶活性的严格调控。减数分裂各阶段之间没有S期。第二次减数分裂类似于有丝分裂。哺乳动物卵母细胞在染色体排列整齐的情况下会持续停滞在中期II，这是由于细胞静止因子（CSF）的活性所致。SAC已在精子发生和卵子发生中被鉴定出来，但性别差异可能导致对非整倍体原的性别特异性差异反应。哺乳动物卵母细胞中SAC成分表达随年龄的降低可能与纺锤体和其他细胞器功能障碍协同作用，以及姐妹染色单体之间部分黏连丧失，使卵母细胞易发生染色体分离错误。这可能会影响对非整倍体原的剂量反应。鉴于高龄产妇生育的趋势，开展关于衰老对人类卵母细胞易受非整倍体原诱导减数分裂错误影响的后果的研究，并建立模型来评估环境暴露对人类健康的风险似乎很有意义。
