OF WORK: Cells respond to environmental toxins by altering their pattern of gene expression, so as to adapt to stress imposed by the exposure. In the DNA repair field, this response is known as the """"""""adaptive response,"""""""" through the elegant work of Samson and Cains, Sekiguchi et al., Samson and Schwartz and others. The base excision repair proteins in mammalian cells have been recognized as adaptive response proteins in recent years. For example, our laboratory discovered that DNA polymerase beta gene expression in rodent cells is up-regulated after cells are exposed to a DNA alkylating agent or to oxidative stress. This up-regulation is, in part, at the transcriptional level and is due to an increase in RNA polymerase II binding and synthesis at the DNA polymerase beta promoter. In the case of MNNG exposure, this increase in activity of RNA polymerase II is due to phosphorylation of the DNA polymerase beta promoter transcriptional activator CREB-1. Such phosphorylation of CREB-1 causes it to become far more active in helping RNA polymerase II function at the DNA polymerase beta promoter's start site. This effect requires DNA alkylation at the O^6 position of G residues. Therefore, phosphorylation of CREB-1 after treatment of cells with an alkylation agent appears to be linked to DNA damage. We are studying both the mechanism of the activated CREB-1 effect on RNA polymerase II and the pathway by which DNA damage signals phosphorylation of CREB-1. We are also studying ways of altering a cell's response to a genotoxic agent by making use of known adaptive responses. For example, up-regulation of base excision repair proteins through treatment of cells with an oxidative stress agent has been found to lower cell sensitivity to DNA alkylating agents such as MMS and MNNG. A cell's response to a DNA damaging agent can also be regulated by """"""""lesion bypass"""""""" mechanisms, such that more DNA lesion by-pass can make a cell less sensitive to a DNA damaging agent. We have found that lesion by-pass mechanisms appear to involve BER pathways as well as other DNA repair pathway.
