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


Authors: Mouery, B. L.; Baker, E. M.; Mei, L.; Wolff, S. C.; Mills, C. A.; Fleifel, D.; Mulugeta, N.; Herring, L. E.; Cook, J. G.
Article Title: APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor–induced arrest
Abstract: 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. Copyright © 2024 the Author(s). Published by PNAS.
Keywords: genetics; pyridines; cell cycle protein; metabolism; cell cycle proteins; cell cycle s phase; breast cancer; drug effect; cell line, tumor; transcription factor e2f; tumor cell line; cell cycle arrest; cell cycle checkpoint; piperazines; cycline; piperazine derivative; cyclins; s phase; cyclin dependent kinase 4; pyridine derivative; f-box proteins; cyclin-dependent kinase 4; cyclin dependent kinase 6; cyclin-dependent kinase 6; anaphase promoting complex; f box protein; e2f transcription factors; cell cycle checkpoints; cdk4 protein, human; humans; human; palbociclib; genome instability; cdk6 protein, human; anaphase promoting complex/cyclosome (apc/c); cyclin-dependent kinase 4/6 (cdk4/6); anaphase-promoting complex-cyclosome; fbxo5 protein, human
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 121
Issue: 30
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2024-07-23
Start Page: e2319574121
Language: English
DOI: 10.1073/pnas.2319574121
PUBMED: 39024113
PROVIDER: scopus
PMCID: PMC11287123
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Eliyambuya Marguerite Baker
    1 Baker