Alternative CDC20 translational isoforms tune mitotic arrest duration
Alternative CDC20 translational isoforms tune mitotic arrest duration
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DOI：
10.1038/s41586-023-05943-7
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发表时间：
2023-04-26
期刊：
影响因子：
64.8
通讯作者：
Cheeseman，Iain M.
中科院分区：
文献类型：
--
作者：
Tsang，Mary-Jane;Cheeseman，Iain M.
有丝分裂缺陷激活纺锤体组装检查点，其抑制后期促进复合物共激活剂CDC 20以诱导延长的细胞周期停滞。一旦错误被纠正，纺锤体组装检查点就被沉默，允许后期开始发生。然而，在存在持续的无法解决的错误的情况下，细胞可以经历“有丝分裂滑移”，退出有丝分裂进入四倍体G1状态，并逃避因长时间停滞而导致的细胞死亡。使细胞能够平衡这些有丝分裂停滞和滑动行为的分子逻辑仍然不清楚。在这里，我们表明，人类细胞调节其有丝分裂停滞的持续时间，通过保守的，替代的CDC 20翻译亚型的存在。下游翻译起始导致截短的CDC 20同种型，其抵抗纺锤体组装检查点介导的抑制，并且即使在存在有丝分裂扰动的情况下也促进有丝分裂退出。我们的研究支持了一个模型，其中CDC 20翻译亚型的相对水平控制有丝分裂停滞的持续时间。在长时间的有丝分裂停滞期间，新的蛋白质合成和差异CDC 20同种型周转产生计时器，一旦截短的Met43同种型达到足够的水平，就发生有丝分裂退出。改变CDC20亚型比例或其翻译控制的靶向分子变化或天然存在的癌症突变调节有丝分裂停滞持续时间和抗有丝分裂药物敏感性，对人类癌症的诊断和治疗具有潜在意义。
Mitotic defects activate the spindle-assembly checkpoint, which inhibits the anaphase-promoting complex co-activator CDC20 to induce a prolonged cell cycle arrest,. Once errors are corrected, the spindle-assembly checkpoint is silenced, allowing anaphase onset to occur. However, in the presence of persistent unresolvable errors, cells can undergo ‘mitotic slippage’, exiting mitosis into a tetraploid G1 state and escaping the cell death that results from a prolonged arrest. The molecular logic that enables cells to balance these duelling mitotic arrest and slippage behaviours remains unclear. Here we demonstrate that human cells modulate the duration of their mitotic arrest through the presence of conserved, alternative CDC20 translational isoforms. Downstream translation initiation results in a truncated CDC20 isoform that is resistant to spindle-assembly-checkpoint-mediated inhibition and promotes mitotic exit even in the presence of mitotic perturbations. Our study supports a model in which the relative levels of CDC20 translational isoforms control the duration of mitotic arrest. During a prolonged mitotic arrest, new protein synthesis and differential CDC20 isoform turnover create a timer, with mitotic exit occurring once the truncated Met43 isoform achieves sufficient levels. Targeted molecular changes or naturally occurring cancer mutations that alter CDC20 isoform ratios or its translational control modulate mitotic arrest duration and anti-mitotic drug sensitivity, with potential implications for the diagnosis and treatment of human cancers.