p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint.
Cdk1 was proposed to compensate for the loss of Cdk2. Here we present evidence that this is possible due to premature translocation of Cdk1 from the cytoplasm to the nucleus in the absence of Cdk2. We also investigated the consequence of loss of Cdk2 on the maintenance of the G1/S DNA damage checkpoint. Cdk2(-/-) mouse embryonic fibroblasts in vitro as well as regenerating liver cells after partial hepatectomy (PH) in Cdk2(-/-) mice, arrest promptly at the G1/S checkpoint in response to gamma-irradiation due to activation of p53 and p21 inhibiting Cdk1. Furthermore re-entry into S phase after irradiation was delayed in Cdk2(-/-) cells due to prolonged and impaired DNA repair activity. In addition, Cdk2(-/-) mice were more sensitive to lethal irradiation compared to wild-type and displayed delayed resumption of DNA replication in regenerating liver cells. Our results suggest that the G1/S DNA damage checkpoint is intact in the absence of Cdk2, but Cdk2 is important for proper repair of the damaged DNA.
Satyanarayana
Ande
A
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA.
Hilton
Mary Beth
MB
Kaldis
Philipp
P
D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002467:Cell Nucleus / Q000201:enzymology / Q000528:radiation effects; D051357:Cyclin-Dependent Kinase 2 / Q000172:deficiency*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology / Q000528:radiation effects; D016193:G1 Phase / Q000528:radiation effects; D005720:Gamma Rays; D051379:Mice; D021381:Protein Transport / Q000528:radiation effects; D011836:Radiation Tolerance / Q000528:radiation effects; D016196:S Phase / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2