FBXW7, which encodes a substrate specific receptor of an SCF E3 ligase complex, is a frequently mutated human tumor suppressor gene known to regulate the post-translational stability of various proteins involved in cellular proliferation. Here, using genome-wide CRISPR screens we report a novel synthetic lethal genetic interaction between FBXW7 and CCNL1 and describe CCNL1 as a new substrate of the SCF-FBXW7 E3 ligase. Further analysis showed that the CCNL1-CDK11 complex is critical at the G2-M phase of the cell cycle since defective CCNL1 accumulation, resulting from FBXW7 mutation, leads to shorter mitotic time. Cells harboring FBXW7 loss-of-function mutations are hypersensitive to treatment with a CDK11 inhibitor, highlighting a genetic vulnerability that could be leveraged for cancer treatment.

中文翻译：

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SCF-FBXW7 通过控制 CCNL1 泛素化调节 G2-M 进展

FBXW7 编码 SCF E3 连接酶复合物的底物特异性受体，是一种经常突变的人类肿瘤抑制基因，已知可调节参与细胞增殖的各种蛋白质的翻译后稳定性。在这里，我们使用全基因组 CRISPR 筛选报告了 FBXW7 和 CCNL1 之间的新型合成致死遗传相互作用，并将 CCNL1 描述为 SCF-FBXW7 E3 连接酶的新底物。进一步的分析表明，CCNL1-CDK11 复合物在细胞周期的 G2-M 期至关重要，因为由 FBXW7 突变引起的有缺陷的 CCNL1 积累会导致有丝分裂时间缩短。携带 FBXW7 功能丧失突变的细胞对使用 CDK11 抑制剂治疗过敏，突出了可用于癌症治疗的遗传易感性。