PT  - JOURNAL ARTICLE
AU  - Jeffrey C. Medley
AU  - Joseph R. DiPanni
AU  - Luke Schira
AU  - Blake M. Shaffou
AU  - Brandon M. Sebou
AU  - Mi Hye Song
TI  - APC/C<sup>FZR-1</sup> Controls ZYG-1 Levels to Regulate Centrosome Assembly
AID  - 10.1101/2020.08.12.248658
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.08.12.248658
4099  - http://biorxiv.org/content/early/2021/05/23/2020.08.12.248658.short
4100  - http://biorxiv.org/content/early/2021/05/23/2020.08.12.248658.full
AB  - Aberrant centrosome numbers are associated with human cancers. The levels of centrosome regulators positively correlate with centrosome number. Thus, tight control of centrosome protein levels is critical. In Caenorhabditis elegans, the anaphase-promoting complex/cyclosome and co-activator FZR-1 (APC/CFZR-1) ubiquitin ligase negatively regulates centrosome assembly through SAS-5 degradation. In this study, we identify the C. elegans ZYG-1 (Plk4 in human) as a new substrate of APC/CFZR-1. Inhibiting APC/CFZR-1 or mutating a ZYG-1 destruction (D)-box leads to elevated ZYG-1 levels at centrosomes, restoring bipolar spindles and embryonic viability to zyg-1 mutants, suggesting that APC/CFZR-1 targets ZYG-1 for proteasomal degradation via D-box motif. We also show the Slimb/βTrCP-binding (SB) motif is critical for ZYG-1 degradation, substantiating a conserved mechanism by which ZYG-1/Plk4 stability is regulated by SCFSlimb/βTrCP-dependent proteolysis via the conserved SB motif in C. elegans. Furthermore, inhibiting both APC/CFZR-1 and SCFSlimb/βTrCP, by co-mutating ZYG-1 SB and D-box motifs, stabilizes ZYG-1 in an additive manner, conveying that APC/CFZR-1 and SCFSlimb/βTrCP ubiquitin ligases function cooperatively for timely ZYG-1 destruction in C. elegans embryos where ZYG-1 activity remains at threshold level to ensure normal centrosome number.Competing Interest StatementThe authors have declared no competing interest.