SCFFBXW7 regulates G2-M progression through control of CCNL1 ubiquitination

EMBO Rep. 2022 Dec 6;23(12):e55044. doi: 10.15252/embr.202255044. Epub 2022 Oct 24.


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.

Keywords: CDK11; FBXW7; cell cycle; cyclin L1; mitosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclins* / metabolism
  • F-Box-WD Repeat-Containing Protein 7* / genetics
  • Humans
  • Mutation
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitination


  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Ubiquitin-Protein Ligases
  • CCNL1 protein, human
  • Cyclins