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Mutagenesis Advance Access originally published online on February 10, 2008
Mutagenesis 2008 23(2):131-136; doi:10.1093/mutage/gen001
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© The Author 2008. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

p53-dependent global nucleotide excision repair of cisplatin-induced intrastrand cross links in human cells

Sara Bhana1, Alan Hewer2, David H. Phillips2 and Daniel R. Lloyd1,*

1Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK 2Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

Cisplatin is an extremely effective chemotherapeutic agent used for the treatment of testicular and other solid tumours. It induces a variety of structural modifications in DNA, the most abundant being the GpG- and ApG-1,2-intrastrand cross links formed between adjacent purine bases. These cross links account for ~90% of cisplatin-induced DNA damage and are thought to be responsible for the cytotoxic activity of the drug. In human cells, the nucleotide excision repair (NER) process removes the intrastrand cross links from the genome, the efficiency of which is likely to be an important determinant of cisplatin cytotoxicity. We have investigated whether the p53 tumour suppressor status affects global NER of cisplatin-induced intrastrand cross links in human cells. We have used a 32P-postlabelling method to monitor the removal of GpG- and ApG-intrastrand cross links from two human cell models (the 041TR system, in which p53 is regulated by a tetracycline-inducible promoter, together with WI38 fibroblasts and the SV40-transformed derivative VA13) that each differ in p53 status. We demonstrate that the absence of functional p53 leads to persistence of both cisplatin-induced intrastrand cross links in the genome, suggesting that p53 regulates NER of these DNA lesions. This observation extends the role of p53 in NER beyond enhancing the removal of environmentally induced DNA lesions to include those of clinical origin. Given the frequency of p53 mutations in human tumours, these results may have implications for the use of cisplatin in cancer chemotherapy.

* To whom correspondence should be addressed. Tel: +44 1227 827357; Fax: +44 1227 763912; Email: D.Lloyd{at}kent.ac.uk

Received on August 21, 2007; revised on December 20, 2007; accepted on January 2, 2008.


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