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

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
Issue number6
Pages (from-to)915-26
Number of pages12
Publication statusPublished - 23 Sep 2005
Externally publishedYes

    Research areas

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

ID: 124903650