DNA repair plays a key role in the prevention of carcinogenesis and mutagenesis. Defective DNA repair has been implicated in various human hereditary disorders that predispose affected individuals to cancer. This article reviews our current understanding of one of major DNA repair systems--the nucleotide excision repair pathway--with special emphasis on the novel findings that have emerged from molecular genetic analysis of yeast and cultured mammalian cells.
Nuclear proteins encoded by both cellular oncogenes and DNA tumor viruses enable activated ras oncogenes to transform a variety of cell types to a tumorigenic state. The interactions are complementary, suggesting that collaborating oncogenes release cells from controls that preclude transformation by ras alone. The nuclear oncoproteins bind both protein and nucleic acid targets and affect processes important in transcription and cell cycle control. Transforming collaborations between oncogenes provide a genetic context to study biochemical interactions involved in normal growth control and to identify mechanisms important in multistep carcinogenesis.
Approximately 50% of human breast tumors secrete a small cysteine-rich protein called pS2. In the human breast cancer cell line MCF-7, expression of the pS2 protein is strongly induced by estrogen, and cloning and sequence analysis of the pS2 gene has revealed an "estrogen responsive element" in the gene's 5'-flanking region. The results of immunohistochemical assays and radioimmunoassays on breast cancer biopsies indicate that the pS2 protein is a marker for hormone-dependent breast tumors and that its expression is associated with longer overall, and disease-free, survival. The pS2 protein is also expressed in normal stomach mucosa and in regenerative tissues in ulcerative diseases of the gastrointestinal tract. Its physiological function is unknown.
The anticancer drug cisplatin exerts its action as a consequence of interaction with DNA. Cell cycle progression facilitates sensitivity to the drug, but inhibition of DNA synthesis is not necessarily the critical step. Lethally damaged cells can progress to and arrest for several days in the G2 phase of the cell cycle before dying. Certain features of cisplatin-induced cell death, such as chromatin condensation and the activation of a DNA endonuclease, are reminiscent of apoptosis, or programmed cell death. Many other anticancer drugs produce the same phenotypic effects, suggesting that these agents may all interact with the same signal transduction pathway leading to cell death.
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