# FBXW7 E3 ligase prevents centriole overduplication by degrading the Plk4 phosphorylated STIL-SAS6 cartwheel assembly

## TL;DR

This study reveals how the FBXW7 protein prevents excessive centriole duplication by breaking down a key complex involved in centriole assembly.

## Contribution

The novel finding is that FBXW7 uses phosphorylation to both assemble and degrade the STIL-SAS6 complex, balancing centriole duplication.

## Key findings

- FBXW7 prevents centriole overduplication by degrading the STIL-SAS6 complex.
- Plk4 phosphorylation of STIL stabilizes FBXW7 binding and promotes degradation.
- FBXW7 expression is negatively correlated with aneuploidy in cancer cells.

## Abstract

Uncontrolled centriole duplication leads to centrosome amplification and chromosomal instability, but its underlying mechanism is poorly understood. A new centriole is duplicated from a cartwheel-like structure assembled by Plk4-phosphorylated SCL/TAL1-interrupting locus (STIL) and its associated SAS6. Here, we show that depletion of SCF E3 ubiquitin ligase, FBXW7 induces prematured duplication of centrioles via excessive stabilization of STIL-SAS6 axis. FBXW7 mediates degradation of STIL-SAS6 axis, and Plk4 kinase activity is required for this degradation. Interestingly, phosphorylation of key Plk4-targeting sites in STIL that drives new centriole assembly by facilitating STIL-SAS6 interaction also stabilizes FBXW7 binding to STIL and promotes degradation of the STIL–SAS6 complex, thus revealing an opposing molecular mechanism to inhibit centriole overduplication. Genomic analyses of cancer cell line data reveal a negative correlation between FBXW7 expression and aneuploidy, as well as a positive correlation between FBXW7 and STIL expression at the mRNA level. Our results thus contribute to improved understanding of the molecular basis of centrosome amplification and aneuploidy.