小柯机器人

美国麻省理工学院Iain M. Cheeseman研究小组发现，可变的CDC20翻译亚型调控有丝分裂停滞时间。这一研究成果于2023年4月26日在线发表在国际学术期刊《自然》上。

研究人员证明，人类细胞通过保守的可变CDC20翻译亚型的存在来调节其有丝分裂停滞的时间。下游翻译启动的结果是截断的CDC20亚型，它对纺锤体组装检查点介导的抑制有耐受，即使在有丝分裂扰动的情况下也能促进有丝分裂的退出。这项研究支持一个模型，其中CDC20翻译亚型的相对水平控制着有丝分裂停滞的持续时间。在漫长的有丝分裂停滞期间，新的蛋白质合成和不同的CDC20亚型周转形成了一个定时器，一旦截断的Met43异构体达到足够的水平，就会发生有丝分裂退出。改变CDC20亚型比例或其翻译控制的靶向分子变化或自然发生的癌症突变会调节有丝分裂停滞持续时间和抗有丝分裂药物敏感性，这对人类癌症的诊断和治疗具有潜在的意义。

据了解，有丝分裂的缺陷激活了纺锤体组装检查点，该检查点抑制了后期促进复合体的共同激活剂CDC20，从而诱发了长时间的细胞周期停止。一旦错误得到纠正，纺锤体组装检查点就会被沉默，从而使后期开始发生。然而，在持续存在无法解决的错误的情况下，细胞可以发生“有丝分裂打滑”，退出有丝分裂进入四倍体G1状态，并逃避长期停滞导致的细胞死亡。使细胞能够平衡这些对立的有丝分裂停滞和打滑行为的分子逻辑仍不清楚。

附：英文原文

Title: Alternative CDC20 translational isoforms tune mitotic arrest duration

Author: Tsang, Mary-Jane, Cheeseman, Iain M.

Issue&Volume: 2023-04-26

Abstract: Mitotic defects activate the spindle-assembly checkpoint, which inhibits the anaphase-promoting complex co-activator CDC20 to induce a prolonged cell cycle arrest1,2. 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.

DOI: 10.1038/s41586-023-05943-7

Source: https://www.nature.com/articles/s41586-023-05943-7

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