APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor–induced arrest

细胞周期蛋白 细胞周期蛋白依赖激酶 细胞周期蛋白A2 细胞周期蛋白D 细胞生物学 细胞周期蛋白B 泛素连接酶 细胞周期 细胞周期检查点 周期素 生物 细胞周期蛋白B1 G1期 细胞周期蛋白 癌症研究 分子生物学 细胞周期蛋白依赖激酶1 泛素 生物化学 细胞 基因
作者
Brandon L. Mouery,E. Baker,Mei Liu,Samuel C. Wolff,Christine A. Mills,Dalia Fleifel,Nebyou Mulugeta,Laura E. Herring,Jeanette Gowen Cook
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [Proceedings of the National Academy of Sciences]
卷期号:121 (30)
标识
DOI:10.1073/pnas.2319574121
摘要

Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.
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