A model for CDK2 in maintaining genomic stability.
Abundant CDK2/cyclin A activity is present in human cancer cells, suggesting that rapid S phase CDK2 inhibition would be an effective anti-cancer approach. The dynamic change of chromatin-loading and -dissociation of MCM proteins requires S phase CDK2 activity. CDK2 inhibition during replication leads to increased MCM complex association with DNA and triggers rereplication. Overreplication-induced DSB and RPA-ssDNA intermediates activate ATM and ATR, resulting in a p53 response which selectively deletes cells with unresolved rereplication.
Zhu
Yonghong
Y
Department of Discovery Research, DNAX Research, Incorporated, Palo Alto, California 94304, USA. Yonghong.zhu@dnax.org
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D008957:Models, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D016196:S Phase / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D019925:Cyclin A; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D004247:DNA; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2