Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair.
In mammalian cells, DNA damage increases the levels of the nuclear tumour-suppressor p53, resulting in elevated synthesis of p21, an inhibitor of cyclin-dependent kinases (CDK). p21 may also directly block DNA replication by inhibiting the proliferating-cell nuclear antigen (PCNA), an essential DNA replication protein. However, PCNA is also required for nucleotide-excision repair of DNA, an intrinsic part of the cellular response to ultraviolet irradiation. Using an in vitro system, we now show that p21 does not block PCNA-dependent nucleotide-excision repair, in contrast to its inhibition of simian virus 40 DNA replication. Furthermore, the short gap-filling DNA synthesis by PCNA-dependent DNA polymerases delta and epsilon is less sensitive to inhibition by p21 than is long primer-extension synthesis. The ability of p21 to inhibit the role of PCNA in DNA replication but not in DNA repair rationalizes in vivo data showing that genetic damage leads to inactivation of chromosomal replication while allowing damage-responsive repair.
Li
R
R
Cold Spring Harbor Laboratory, New York 11724.
Waga
S
S
Hannon
G J
GJ
Beach
D
D
Stillman
B
B
D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D004260:DNA Repair; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D013539:Simian virus 40 / Q000235:genetics; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D004259:DNA-Directed DNA Polymerase