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

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.

SUBMITTER: O'Brien S

PROVIDER: S-EPMC9724663 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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SCFFBXW7 regulates G2-M progression through control of CCNL1 ubiquitination.

O'Brien Siobhan S Kelso Susan S Steinhart Zachary Z Orlicky Stephen S Mis Monika M Kim Yunhye Y Lin Sichun S Sicheri Frank F Angers Stephane S

EMBO reports 20221024 12

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 ...[more]

PMID: 36278408

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