Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1

Birgit Otzen Petersen, Christian Wagener, Federica Marinoni, Edgar R. Kramer, Marina Melixetian, Eros Lazzerini Denchi, Christian Gieffers, Cristian Matteucci, Jan Michael Peters, Kristian Helin

Research output: Contribution to journalArticle

Abstract

CDC6 is conserved during evolution and is essential and limiting for the initiation of eukaryotic DNA replication. Human CDC6 activity is regulated by periodic transcription and CDK-regulated subcellular localization. Here, we show that, in addition to being absent from nonproliferating cells, CDC6 is targeted for ubiquitin-mediated proteolysis by the anaphase promoting complex (APC)/cyclosome in G1. A combination of point mutations in the destruction box and KEN-box motifs in CDC6 stabilizes the protein in G1 and in quiescent cells. Furthermore, APC, in association with CDH1, ubiquitinates CDC6 in vitro, and both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo. Although a stable mutant of CDC6 is biologically active, overexpression of this mutant or wild-type CDC6 is not sufficient to induce multiple rounds of DNA replication in the same cell cycle. The APC-CDH1-dependent proteolysis of CDC6 in early G1 and in quiescent cells suggests that this process is part of a mechanism that ensures the timely licensing of replication origins during G1.

Original languageEnglish
Pages (from-to)2330-2343
Number of pages14
JournalGenes and Development
Volume14
Issue number18
DOIs
Publication statusPublished - Sep 15 2000

Keywords

  • APC
  • CDC6
  • Cell cycle
  • DNA replication
  • Proteolysis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Petersen, B. O., Wagener, C., Marinoni, F., Kramer, E. R., Melixetian, M., Denchi, E. L., Gieffers, C., Matteucci, C., Peters, J. M., & Helin, K. (2000). Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. Genes and Development, 14(18), 2330-2343. https://doi.org/10.1101/gad.832500