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APC/CFZR-1 Controls ZYG-1 Levels to Regulate Centrosome Assembly

View ORCID ProfileJeffrey C. Medley, View ORCID ProfileJoseph R. DiPanni, View ORCID ProfileLuke Schira, View ORCID ProfileBlake M. Shaffou, View ORCID ProfileBrandon M. Sebou, View ORCID ProfileMi Hye Song
doi: https://doi.org/10.1101/2020.08.12.248658
Jeffrey C. Medley
1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
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Joseph R. DiPanni
1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
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Luke Schira
1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
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Blake M. Shaffou
1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
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Brandon M. Sebou
1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
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Mi Hye Song
1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
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  • For correspondence: msong2@oakland.edu
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Abstract

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 Statement

The authors have declared no competing interest.

Footnotes

  • Fig1-3 revised; Supplemental files updated.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 23, 2021.
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APC/CFZR-1 Controls ZYG-1 Levels to Regulate Centrosome Assembly
Jeffrey C. Medley, Joseph R. DiPanni, Luke Schira, Blake M. Shaffou, Brandon M. Sebou, Mi Hye Song
bioRxiv 2020.08.12.248658; doi: https://doi.org/10.1101/2020.08.12.248658
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APC/CFZR-1 Controls ZYG-1 Levels to Regulate Centrosome Assembly
Jeffrey C. Medley, Joseph R. DiPanni, Luke Schira, Blake M. Shaffou, Brandon M. Sebou, Mi Hye Song
bioRxiv 2020.08.12.248658; doi: https://doi.org/10.1101/2020.08.12.248658

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