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首页> 外文期刊>Molecular cell >Destruction of claspin by SCF beta TrCP restrains Chk1 activation and facilitates recovery from genotoxic stress
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Destruction of claspin by SCF beta TrCP restrains Chk1 activation and facilitates recovery from genotoxic stress

机译：SCF beta TrCP破坏claspin抑制Chk1激活并促进从遗传毒性应激中恢复

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摘要

We show that Claspin, an adaptor protein required for Chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the SCF beta TrCP ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the PIk1 kinase and the integrity of a beta TrCP recognition motif (phosphodegron) in the N terminus of Claspin. Uncoupling of Claspin from beta TrCP by mutating the conserved serines in Claspin's phosphodegron or by knocking down beta TrCP stabilized Claspin in mitosis, impaired Chk1 dephosphorylation, and delayed G2/M transition during recovery from cell cycle arrest imposed by DNA damage or replication stress. Moreover, the inability to degrade Claspin allowed partial reactivation of Chk1 in cells exposed to DNA damage after passing the G2/M transition. Our data suggest that degradation of Claspin facilitates timely reversal of the checkpoint response and delineates the period permissive for Chk1 activation during cell cycle progression.
机译：我们显示，Claspin，Chk1激活所需的衔接蛋白，在有丝分裂开始时会降解。 Claspin降解是由其与SCFβTrCP泛素连接酶相互作用和泛素化引起的。这种相互作用是依赖于磷酸化的，并要求PIk1激酶的活性和在Claspin的N末端的βTrCP识别基序（phosphodegron）的完整性。通过突变Claspin的磷酸脱氢酶中保守的丝氨酸或敲除βTrCP稳定的Claspin的有丝分裂，削弱Chk1的去磷酸化作用以及从DNA损伤或复制压力导致的细胞周期停滞恢复中延迟的G2 / M过渡，使Claspin与βTrCP脱钩。此外，由于无法降解Claspin，在经过G2 / M转变后，暴露于DNA损伤的细胞中的Chk1部分活化。我们的数据表明，Claspin的降解有助于及时逆转检查点反应，并描绘出细胞周期进程中允许Chk1激活的时间段。

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