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首页> 外文期刊>Molecular and Cellular Biology >Nonperiodic Activity of the Human Anaphase-Promoting Complex–Cdh1 Ubiquitin Ligase Results in Continuous DNA Synthesis Uncoupled from Mitosis
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Nonperiodic Activity of the Human Anaphase-Promoting Complex–Cdh1 Ubiquitin Ligase Results in Continuous DNA Synthesis Uncoupled from Mitosis

机译：人类后期促进复合物-Cdh1泛素连接酶的非周期性活动导致连续DNA合成与有丝分裂分离。

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Ubiquitin-proteasome-mediated destruction of rate-limiting proteins is required for timely progression through the main cell cycle transitions. The anaphase-promoting complex (APC), periodically activated by the Cdh1 subunit, represents one of the major cellular ubiquitin ligases which, in Saccharomyces cerevisiae andDrosophila spp., triggers exit from mitosis and during G1 prevents unscheduled DNA replication. In this study we investigated the importance of periodic oscillation of the APC-Cdh1 activity for the cell cycle progression in human cells. We show that conditional interference with the APC-Cdh1 dissociation at the G1/S transition resulted in an inability to accumulate a surprisingly broad range of critical mitotic regulators including cyclin B1, cyclin A, Plk1, Pds1, mitosin (CENP-F), Aim1, and Cdc20. Unexpectedly, although constitutively assembled APC-Cdh1 also delayed G1/S transition and lowered the rate of DNA synthesis during S phase, some of the activities essential for DNA replication became markedly amplified, mainly due to a progressive increase of E2F-dependent cyclin E transcription and a rapid turnover of the p27Kip1 cyclin-dependent kinase inhibitor. Consequently, failure to inactivate APC-Cdh1 beyond the G1/S transition not only inhibited productive cell division but also supported slow but uninterrupted DNA replication, precluding S-phase exit and causing massive overreplication of the genome. Our data suggest that timely oscillation of the APC-Cdh1 ubiquitin ligase activity represents an essential step in coordinating DNA replication with cell division and that failure of mechanisms regulating association of APC with the Cdh1 activating subunit can undermine genomic stability in mammalian cells.
机译：遍在蛋白-蛋白酶体介导的限速蛋白的破坏是通过主要细胞周期过渡及时进展所必需的。 Cdh1亚基周期性激活的后期促进复合物（APC）代表了主要的细胞泛素连接酶之一，在酿酒酵母（Saccharomyces cerevisiae）和果蝇（Drosophila）中，它们触发了出口。从有丝分裂和G 1 期间防止意外的DNA复制。在这项研究中，我们研究了APC-Cdh1活性的周期性振荡对于人类细胞中细胞周期进程的重要性。我们显示，在G 1 / S过渡处对APC-Cdh1解离的条件干扰导致无法积累令人惊讶的广泛范围的关键有丝分裂调节剂，包括细胞周期蛋白B1，细胞周期蛋白A，Plk1，Pds1， mitosin（CENP-F），Aim1和Cdc20。出乎意料的是，尽管组成性组装的APC-Cdh1也延迟了G 1 / S的转变并降低了S期的DNA合成速率，但DNA复制必不可少的一些活性却显着扩增，这主要是由于进行性依赖E2F的细胞周期蛋白E转录的增加和p27 Kip1 依赖细胞周期蛋白的激酶抑制剂的快速更新。因此，未能使APC-Cdh1失活超过G 1 / S过渡，不仅抑制了生产力的细胞分裂，而且还支持缓慢但不间断的DNA复制，从而阻止了S期退出并导致基因组大量过度复制。我们的数据表明，及时振荡APC-Cdh1泛素连接酶活性是协调DNA复制与细胞分裂的必不可少的步骤，而调节APC与Cdh1激活亚基缔合的机制失败会破坏哺乳动物细胞的基因组稳定性。

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