Cell fate decision upon prolonged mitotic arrest induced by microtubule-targeting agents depends on the activity of the tumor suppressor and F-box protein FBXW7. FBXW7 promotes mitotic cell death and prevents premature escape from mitosis through mitotic slippage. Mitotic slippage is a process that can cause chemoresistance and tumor relapse. Therefore, understanding the mechanisms that regulate the balance between mitotic cell death and mitotic slippage is an important task. Here we report that FBXW7 protein levels markedly decline during extended mitotic arrest. FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically under a prolonged delay in mitosis, leading to ubiquitylation and subsequent proteasomal degradation of FBXW7 by the FBXO45-MYCBP2 E3 ubiquitin ligase. Moreover, we find that FBXO45-MYCBP2 counteracts FBXW7 in that it promotes mitotic slippage and prevents cell death in mitosis. Targeting this interaction represents a promising strategy to prevent chemotherapy resistance.
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We thank B.E. Clurman, D. Gerlich, L. Hengst, F. Melchior, G. Melino, J.D. Parvin, A. Peschiaroli, and K. Scholich for providing reagents and cell lines. We acknowledge the DKFZ Mass Spectrometry and Microscopy Core Facilities for providing equipment and excellent technical assistance. We thank Bettina Dörr for expert technical assistance. We acknowledge the members of our lab for critically reading the manuscript.
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Richter, K.T., Kschonsak, Y.T., Vodicska, B. et al. FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation. Cell Death Differ 27, 758–772 (2020). https://doi.org/10.1038/s41418-019-0385-7
Cell Death Discovery (2020)