CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis
- PMID: 16153703
- DOI: 10.1016/j.cell.2005.08.013
CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis
Abstract
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.
Comment in
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CDKs give Cdc6 a license to drive into S phase.Cell. 2005 Sep 23;122(6):825-7. doi: 10.1016/j.cell.2005.09.001. Cell. 2005. PMID: 16179249 Review.
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