Radiation-induced DNA Damage and Transcriptional Mutagenesis in Tumor Development

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DESCRIPTION (provided by applicant): The genes of all cells are continuously damaged by extrinsic agents such as radiation and chemicals as well as endogenous, spontaneous processes. DMA damage, if left unrepaired, can result in a number of deleterious biological consequences, including the production of mutant proteins that can change the cellular phenotype. Delineating the processes that generate mutant proteins is of great importance for our understanding of the endpoints of genetic damage which include cell death, changes in physiology and, in the case of mammalian cells, tumor development. The vast majorities of DNA damage-induced mutagenesis studies are replication-centric and are based on models of DNA polymerase errors occurring in the vicinity of the lesion. Few studies have addressed the possibility that mutagenesis at the level of transcription (via RNA polymerase encounters with DNA damage) may also be an important pathway for generating mutant proteins, particularly in non-dividing cells. The studies proposed in this project are focused on two major areas: (i) the delineation of the roles that DNA repair excision pathways (in bacterial and mammalian cells) play in transcriptional mutagenesis (TM), and (ii) whether TM can activate a mutant Ras oncogene-mediated signaling pathway related to mammalian tumor development. These studies should substantially increase our understanding of the occurrence and biological relevance of TM as well as provide important insights into the DNA repair systems employed by bacterial and mammalian cells for reversing frequently occurring and ionizing radiation-induced DNA base damages under both growth and non-growth conditions.