SCF FBXW7 regulates G2-M progression through control of CCNL1 ubiquitination.
Siobhan O'BrienSusan KelsoZachary SteinhartStephen OrlickyMonika MisYunhye KimSichun LinFrank SicheriStephane AngersPublished in: EMBO reports (2022)
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.
Keyphrases
- genome wide
- cell cycle
- dna methylation
- copy number
- cell proliferation
- induced apoptosis
- endothelial cells
- crispr cas
- climate change
- signaling pathway
- oxidative stress
- cell cycle arrest
- high throughput
- cell death
- endoplasmic reticulum stress
- genome editing
- single cell
- combination therapy
- structural basis
- genome wide identification