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The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of Histone 3 Lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2022-11-14 , DOI: 10.1016/j.jbc.2022.102703
Simon Hänle-Kreidler 1 , Kai T Richter 1 , Ingrid Hoffmann 2
Affiliation  

During prolonged mitotic arrest induced by anti-microtubule drugs, cell fate decision is determined by two alternative pathways, one leading to cell death, the other inducing premature escape from mitosis by mitotic slippage. FBWX7, a member of the F-box family of proteins and substrate-targeting subunit of the SCF (SKP1-CUL1-F-Box) E3 ubiquitin ligase complex promotes mitotic cell death and prevents mitotic slippage, but molecular details underlying these roles for FBWX7 are unclear. In this study, we report that WDR5, a component of the mixed lineage leukemia (MLL) complex of Histone 3 Lysine 4 (H3K4) methyltransferases, is a substrate of FBXW7. We determined by co-immunoprecipitation experiments and in vitro binding assays that WDR5 interacts with FBXW7 in vivo and in vitro. SCF-FBXW7 mediates ubiquitination of WDR5 and targets it for proteasomal degradation. Furthermore, we find that WDR5 depletion counteracts FBXW7 loss-of-function by reducing mitotic slippage and polyploidization. In conclusion, our data elucidate a new mechanism in mitotic cell fate regulation which might contribute to prevent chemotherapy resistance in patients after anti-microtubule drug treatment.



中文翻译:

SCF-FBXW7 E3 泛素连接酶触发组蛋白 3 赖氨酸 4 甲基转移酶复合物组分 WDR5 的降解以防止有丝分裂滑移

在抗微管药物诱导的长期有丝分裂停滞期间,细胞命运决定由两种替代途径决定,一种导致细胞死亡,另一种通过有丝分裂滑移诱导过早脱离有丝分裂。FBWX7,F-box 蛋白家族的成员和 SCF 的底物靶向亚基 (SKP1-CUL1-F-Box) E3 泛素连接酶复合物促进有丝分裂细胞死亡并防止有丝分裂滑移,但 FBWX7 这些作用背后的分子细节不清楚。在这项研究中,我们报告 WDR5 是组蛋白 3 赖氨酸 4 (H3K4) 甲基转移酶的混合谱系白血病 (MLL) 复合物的一个组成部分,是 FBXW7 的底物。我们通过共免疫沉淀实验和体外结合测定确定 WDR5在体内与 FBXW7 相互作用,并且体外。SCF-FBXW7 介导 WDR5 的泛素化并将其靶向蛋白酶体降解。此外,我们发现 WDR5 耗尽通过减少有丝分裂滑动和多倍体化来抵消 FBXW7 功能丧失。总之,我们的数据阐明了有丝分裂细胞命运调控的新机制,这可能有助于预防抗微管药物治疗后患者的化疗耐药性。

更新日期:2022-11-15
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