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J. Biol. Chem., Vol. 276, Issue 28, 25813-25822, July 13, 2001
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From the Departments of Medicine and Genetics, Division of
Oncology, Stanford University School of Medicine,
Stanford, California 94305
The p53 tumor suppressor gene is a
transcriptional activator involved in cell cycle regulation, apoptosis,
and DNA repair. We have shown that p53 is required for efficient
nucleotide excision repair of UV-induced DNA photoproducts from global
genomic DNA but has no effect on transcription-coupled repair. In order
to evaluate whether p53 influences repair indirectly through cell cycle
arrest following DNA damage or plays a direct role, we examined repair
in vivo in human cells genetically altered to disrupt or regulate the function of p53 and p21. Both primary human
fibroblasts and HCT116 colon carcinoma cells wild type for p53 but in
which the p21 gene was inactivated through targeted homologous
recombination showed no decrease in global repair of UV photoproducts.
Human bladder carcinoma cells mutant for p53 and containing a
tetracycline-regulated p21 cDNA showed no significant enhancement
of repair upon induction of p21 expression. All of the cell lines,
including the mismatch repair-deficient, MLH1 mutant HCT116 cells, were
proficient for transcription-coupled repair. Clonogenic survival of
HCT116 cells following UV irradiation showed no dependence on p21.
Therefore, our results indicate that p53-dependent
nucleotide excision repair does not require the function of the p21
gene product and is independent of p53-regulated cell cycle checkpoints.
To whom correspondence should be addressed: Dept. of
Medicine, Division of Oncology, Stanford University School of
Medicine, 1115 CCSR Bldg., Stanford, CA 94305. Tel.: 650-498-6689;
Fax: 650-725-1420; E-mail: jmf@stanford.edu.
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