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

TY - JOUR

T1 - CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis

AU - Mailand, Niels

AU - Diffley, John F X

PY - 2005/9/23

Y1 - 2005/9/23

N2 - 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.

AB - 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.

KW - Anaphase-Promoting Complex-Cyclosome

KW - Cell Cycle

KW - Cell Cycle Proteins

KW - Cell Line, Tumor

KW - Cyclin-Dependent Kinases

KW - DNA Replication

KW - Humans

KW - Nuclear Proteins

KW - Phosphorylation

KW - Replication Origin

KW - S Phase

KW - Ubiquitin-Protein Ligase Complexes

U2 - 10.1016/j.cell.2005.08.013

DO - 10.1016/j.cell.2005.08.013

M3 - Journal article

C2 - 16153703

SN - 0092-8674

VL - 122

SP - 915

EP - 926

JO - Cell

JF - Cell

IS - 6

ER -