INTERACTION OF THE CYCLIN-DEPENDENT KINAS E INHIBITOR P21 WITH PCNA -A LINK BETWEEN CELL-CYCLE AND DNA-REPAIR

The cyclin-dependent kinase (CDK) inhibitors, or CKIs, play an essenti al role in the control of cell proliferation. CKIs regulate G1/S progr ession through the modulation of cyclin/CDK complexes activity in resp onse to various intracellular or extracellular signals. p21(Cip1), the first CKI identified, plays a key role in growth arrest induced by th e tumor suppressor p53 in response to DNA damage. A unique feature of p21 that distinguishes it from other CKIs is its ability to associate with the proliferating cell nuclear antigen (PCNA), an auxiliary facto r for DNA polymerase delta and epsilon, that is essential for both DNA replication and DNA repair. The association, in non-transformed human cells of p21 with PCNA and various cyclin/CDKs in p21/PCNA/cyclin/CDK quaternary complexes provides an important link between the cell cycl e, DNA replication and DNA repair. p21 contains a C-terminal PCNA bind ing motif that interacts with the interdomain connector loop of PCNA a nd inhibits PCNA-dependent DNA replication and mismatch repair in vitr o. This C-terminal domain might inhibit cell cycle progression indepen dently of the N-terminal CDK inhibitory domain and thus contribute to the antiproliferative activity of p21. In contrast to its inhibitory e ffect on DNA replication and mismatch repair, p21 does not appear to b lock PCNA-dependent nucleotide excision repair. Therefore, p21 inducti on after DNA damage may lead to inhibition of cell cycle progression a nd inactivation of PCNA-dependent DNA replication, while permitting ac tive nucleotide excision repair. Such a mechanism would ensure that an y errors caused by the damage are corrected before being propagated by DNA replication.