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

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.