WEE 1拮抗APC/C^CDH 1活性以促进S期进入
WEE1拮抗APC/C^CDH1活性以促进S期进入
作者： 小柯机器人 发布时间：2026/10/25 20:48:44
本期文章：《自然》：Online/在线发表
2026年10月21日，英国伦敦帝国理工学院Alexis R. Barr等科学家在《自然》发表研究，揭示WEE1通过拮抗APC/C^CDH1活性促进S期进入。
WEE1磷酸化并抑制细胞周期蛋白依赖性激酶的活性，以阻止有丝分裂进入并建立G2 DNA损伤检查点。因此，WEE1抑制剂被开发用于对TP53突变肿瘤实现合成致死，这些肿瘤变得依赖这种WEE1介导的检查点，此类抑制剂正在进行临床试验。然而，WEE1抑制剂在TP53野生型肿瘤中也有疗效，且许多试验因高水平毒副作用而终止，提示WEE1具有未知功能。在此，研究人员表明，WEE1通过拮抗E3泛素连接酶——与CDH1结合的后期促进复合物-环体（APC/C^CDH1）——的活性，促进细胞从静息状态（G0）重新进入细胞周期。WEE1磷酸化CDH1（FZR1）上介导CDH1与APC/C相互作用的关键残基。在G0/G1期WEE1功能丧失的细胞表现出S期进入延迟、G1/S转换受损、细胞周期蛋白依赖性激酶抑制剂p21^Cip1/Kip1在S期异常积累以及p21依赖性G2期阻滞。APC/C^CDH1或p21表达降低使细胞对急性WEE1抑制更敏感，并且这两条通路在获得性WEE1抑制剂耐药细胞中均下调。这些结果揭示了一种细胞周期控制机制，对如何在临床中使用WEE1抑制剂具有启示意义。
附：英文原文
Title: WEE1 opposes APC/CCDH1 activity to promote S phase entry
Author: Vuillemenot, Luc-Alban, Morales, Lucas G., Dragoi, Calin-Mihai, Pennycook, Betheney R., Harris, Edward, Lin, Liuyang C., Weston, William A., Brown, Jade-Ellen, Graham, Emma, Moulin, Leelou, Andrew, Ivan, Roumelioti, Georgia, Montoya, Alex, Game, Laurence, Young, George R., Datta, Keshava K., Shliaha, Pavel, Novk, Bla, Yamano, Hiroyuki, Barr, Alexis R.
Issue&Volume: 2026-10-21
Abstract: WEE1 phosphorylates and inhibits the activity of cyclin-dependent kinases to prevent mitotic entry and establish a G2 DNA damage checkpoint1,2,3. Consequently, WEE1 inhibitors have been developed to be synthetically lethal in TP53-mutated tumours that become reliant on this WEE1-mediated checkpoint, and such inhibitors are undergoing clinical trials. However, WEE1 inhibitors also have efficacy in TP53-wild-type tumours, and many trials have been terminated owing to high levels of toxic side effects, suggesting that WEE1 has unknown functions. Here we show that WEE1 promotes cell cycle re-entry from quiescence (G0) by opposing the activity of the E3 ubiquitin ligase, anaphase-promoting complex–cyclosome bound to CDH1 (APC/CCDH1). WEE1 phosphorylates CDH1 (FZR1) at key residues that mediate the interaction between CDH1 and APC/C. Cells with loss of function of WEE1 during G0/G1 have delayed S phase entry, impaired G1/S transition, abnormal S phase accumulation of cyclin-dependent kinase inhibitor p21Cip1/Kip1 and a p21-dependent G2 arrest. Reduced expression of APC/CCDH1 or p21 renders cells more sensitive to acute WEE1 inhibition, and both pathways are downregulated in cells with acquired WEE1 inhibitor resistance. These results reveal a mechanism of cell cycle control that has implications for how WEE1 inhibitors should be used in the clinic.
DOI: 10.1038/s41586-026-11188-x
Source: https://www.nature.com/articles/s41586-026-11188-x