The DNA templates for transcription are continuously damaged by radiation and chemical agents, as well as by products from endogenous metabolic processes. RNA polymerases encountering DNA damage may result in a number of deleterious biological consequences, such as apoptosis or mutagenesis. Transcriptional mutagenesis may be an important pathway for the generation of mutant proteins, particularly in non-dividing cells. The goal of my research is to understand how errors are avoided in transcription by RNA polymerase II (pol II). I wish to elucidate the structural basis of pol II arrest at DNA damage sites, to investigate the biological consequences of transcription arrest, and to reveal the mechanism of damage-induced transcriptional mutagenesis. My proposed research will also have implications for transcriptional regulation, DNA damage recognition, DNA repair, and rational drug design for cancer and other transcription related human diseases.
