CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis

Cell. 2005 Sep 23;122(6):915-26. doi: 10.1016/j.cell.2005.08.013.


Cyclin-dependent kinases (CDKs) restrict DNA replication origin firing to once per cell cycle by preventing the assembly of prereplicative complexes (pre-RCs; licensing) outside of G1 phase. Paradoxically, under certain circumstances, CDKs such as cyclin E-cdk2 are also required to promote licensing. Here, we show that CDK phosphorylation of the essential licensing factor Cdc6 stabilizes it by preventing its association with the anaphase promoting complex/cyclosome (APC/C). APC/C-dependent Cdc6 proteolysis prevents pre-RC assembly in quiescent cells and, when cells reenter the cell cycle from quiescence, CDK-dependent Cdc6 stabilization allows Cdc6 to accumulate before the licensing inhibitors geminin and cyclin A which are also APC/C substrates. This novel mechanism for regulating protein stability establishes a window of time prior to S phase when pre-RCs can assemble which we propose represents a critical function of cyclin E.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Cell Cycle / physiology
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / metabolism*
  • DNA Replication*
  • Humans
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Replication Origin / genetics
  • Replication Origin / physiology*
  • S Phase
  • Ubiquitin-Protein Ligase Complexes / metabolism*


  • CDC6 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Cyclin-Dependent Kinases