Abstract
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)1–6. p21 may also directly block DNA replication by inhibiting the proliferating-cell nuclear antigen (PCNA)7, an essential DNA replication protein. However, PCNA is also required for nucleotide-excision repair of DNA8, an intrinsic part of the cellular response to ultraviolet irradiation. Using an in vitro system9, we now show that p21 does not block PCNA-dependent nucleotide-excision repair, in contrast to its inhibition of simian virus 40 DNA replication7. Furthermore, the short gap-filling DNA synthesis by PCNA-dependent DNA polymerases δ and ɛ 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.
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Li, R., Waga, S., Hannon, G. et al. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature 371, 534–537 (1994). https://doi.org/10.1038/371534a0
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DOI: https://doi.org/10.1038/371534a0
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