The overall objective of the present proposal is to determine the efficiency of DNA repair in the same DNA sequence before and after the formation of a transcriptionally active chromatin conformation. These studies will entail the use of two isogenic mouse L cell lines which carry the herpes simplex thymidine kinase (tk) gene and mouse mammary tumor virus long terminal repeat (LTR) sequence stably integrated into the mouse genome. Only one and a half copies of this """"""""LTL"""""""" construction are integrated into the genome of these cells and the expression of the tk gene is totally dependent on the presence of glucocorticoid hormone. Furthermore, in the absence of hormone, the LTL region has an """"""""inactive"""""""" chromatin conformation, while shortly after hormone treatment this sequence changes to an active conformation. Thus, we will examine the effects of both gene expression and changes in local chromatin structure on the efficiency of removal of DNA lesions. Since DNA damage by chemical and physical carcinogens may alter the expression of specific genes required for the eventual establishment of the neoplastic phenotype, these studies should provide insight into the cell's defense mechanism for resisting neoplastic transformation.
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