US EPA

1104252 

Journal Article 

Interaction of the cyclin-dependent kinase inhibitor p21 with PCNA: A link between cell cycle and DNA repair 

Cayrol, C; Ducommun, B 

1997 

1 

Médecine Sciences
ISSN: 0767-0974 

13 

11 

French 

The cyclin-dependent kinase (CDK) inhibitors, or CKIs, play an essential role in the control of cell proliferation. CKIs regulate G1/S progression through the modulation of cyclin/CDK complexes activity in response to various intracellular or extracellular signals. p21(Cip1), the first CKI identified, plays a key role in growth arrest induced by the tumor suressor 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 factor 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 cycle, DNA replication and DNA repair. p21 contains a C-terminal PCNA binding motif that interacts with the interdomain connector loop of PCNA and inhibits PCNA-dependent DNA replication and mismatch repair in vitro. This C-terminal domain might inhibit cell cycle progression independently of the N-terminal CDK inhibitory domain and thus contribute to the antiproliferative activity of p21. In contrast to its inhibitory effect on DNA replication and mismatch repair, p21 does not appear to block PCNA-dependent nucleotide excision repair. Therefore, p21 induction after DNA damage may lead to inhibition of cell cycle progression and inactivation of PCNA-dependent DNA replication, while permitting active nucleotide excision repair. Such a mechanism would ensure that any errors caused by the damage are corrected before being propagated by DNA replication.