p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint.
The cyclin-dependent kinase inhibitor p21 is required for a sustained G(2) arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G(2). We show that p21 blocks the activating phosphorylation of Cdc2 on Thr(161). p21 does not interfere with the dephosphorylation of two inhibitory phosphorylation sites on Cdc2, Thr(14) and Tyr(15), indicating that p21 targets a different event in Cdc2 activation as the well described DNA damage checkpoint pathway involving Chk1 and Cdc25C. Taken together our data show that a cell is equipped with at least two independent pathways to ensure efficient inhibition of Cdc2 activity in response to DNA damage, influencing both positive and negative regulatory phosphorylation events on Cdc2.
Smits
V A
VA
Jordan Laboratory, Department of Hematology, University Medical Center Utrecht G03-647, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
Klompmaker
R
R
Vallenius
T
T
Rijksen
G
G
Mäkela
T P
TP
Medema
R H
RH
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism*; D004249:DNA Damage; D016195:G2 Phase; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D013912:Threonine / Q000378:metabolism
D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D013912:Threonine; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases