The cell cycle regulator p27Kip1 interacts with MCM7, a DNA replication licensing factor, to inhibit initiation of DNA replication.
The G1/S phase restriction point is a critical checkpoint that interfaces between the cell cycle regulatory machinery and DNA replicator proteins. Here, we report a novel function for the cyclin-dependent kinase inhibitor p27Kip1 in inhibiting DNA replication through its interaction with MCM7, a DNA replication protein that is essential for initiation of DNA replication and maintenance of genomic integrity. We find that p27Kip1 binds the conserved minichromosome maintenance (MCM) domain of MCM7. The proteins interact endogenously in vivo in a growth factor-dependent manner, such that the carboxyl terminal domain of p27Kip1 inhibits DNA replication independent of its function as a cyclin-dependent kinase inhibitor. This novel function of p27Kip1 may prevent inappropriate initiation of DNA replication prior to S phase.
Nallamshetty
Shriram
S
National Heart, Lung, and Blood Institute, National Institutes of Health, Building 50, Room 4523, 50 Center Drive, Bethesda, MD 20892, USA.
Crook
Martin
M
Boehm
Manfred
M
Yoshimoto
Takanobu
T
Olive
Michelle
M
Nabel
Elizabeth G
EG
D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism* / Q000502:physiology; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016193:G1 Phase; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D020798:Two-Hybrid System Techniques
C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7