Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1

Mol Cell. 2015 Oct 1;60(1):21-34. doi: 10.1016/j.molcel.2015.08.011. Epub 2015 Sep 17.

Abstract

Mutations in the E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Parkin has also been implicated in mitosis through mechanisms that are unclear. Here we show that Parkin interacts with anaphase promoting complex/cyclosome (APC/C) coactivators Cdc20 and Cdh1 to mediate the degradation of several key mitotic regulators independent of APC/C. We demonstrate that ordered progression through mitosis is orchestrated by two distinct E3 ligases through the shared use of Cdc20 and Cdh1. Furthermore, Parkin is phosphorylated and activated by polo-like kinase 1 (Plk1) during mitosis. Parkin deficiency results in overexpression of its substrates, mitotic defects, genomic instability, and tumorigenesis. These results suggest that the Parkin-Cdc20/Cdh1 complex is an important regulator of mitosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism*
  • Carcinogenesis / genetics
  • Cdc20 Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Knockout Techniques
  • Genomic Instability*
  • HEK293 Cells
  • Humans
  • Mice
  • Mitosis*
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Cadherins
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1