Abstract
Nucleotide excision repair provides an important cellular defense against a large variety of structurally unrelated DNA alterations. Most of these alterations, if unrepaired, may contribute to mutagenesis, oncogenesis, and developmental abnormalities, as well as cellular lethality. There are two subpathways of nucleotide excision repair; global genomic repair (GGR) and transcription coupled repair (TCR), that is selective for the transcribed DNA strand in expressed genes. Some of the proteins involved in the recognition of DNA damage (including RNA polymerase) are also responsive to natural variations in the secondary structural features of DNA. Gratuitous repair events in undamaged DNA might then contribute to genomic instability. However, damage recognition enzymes for GGR are normally maintained at very low levels unless the cells are genomically stressed. GGR is controlled through the SOS stress response in E. coli and through the activated p53 tumor suppressor in human cells. These inducible responses in human cells are important, as they have been shown to operate upon chemical carcinogen DNA damage at levels to which humans are environmentally exposed. Interestingly, most rodent tissues are deficient in the p53-dependent GGR pathway. Since rodents are used as surrogates for environmental cancer risk assessment, it is essential that we understand how they differ from humans with respect to DNA repair and oncogenic responses to environmental genotoxins. In the case of terminally differentiated mammalian cells, a new paradigm has appeared in which GGR is attenuated but both strands of expressed genes are repaired efficiently.
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Acknowledgements
The research in my laboratory has been supported by an Outstanding Investigator Grant (CA 44349) and more recently by grants (CA77712, CA91456 and CA90915) from the National Cancer Institute. I am indebted to my students and colleagues, many of whom are cited in the references, for their remarkable contributions to the ideas as well as the experimental results presented in this review. I wish to thank Denise Flowers for her essential help with the manuscript preparation.
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Hanawalt, P. Subpathways of nucleotide excision repair and their regulation. Oncogene 21, 8949–8956 (2002). https://doi.org/10.1038/sj.onc.1206096
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DOI: https://doi.org/10.1038/sj.onc.1206096
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