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bioRxiv · 10.1101/2022.09.26.509608

SCF-FBXW7 regulates G2-M progression through control of CCNL1 ubiquitination

O'Brien, S.·Kelso, S.·Steinhart, Z.·Orlicky, S.·Mis, M.·Kim, Y.·Lin, S.·Sicheri, F.·Angers, S.
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Abstract

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.

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O'Brien, S., Kelso, S., Steinhart, Z., Orlicky, S., Mis, M., Kim, Y., Lin, S., Sicheri, F., Angers, S.. 2022-09-26. SCF-FBXW7 regulates G2-M progression through control of CCNL1 ubiquitination. https://doi.org/10.1101/2022.09.26.509608

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