RNA Polymerase II Transcription: Effects of DNA Damage and DNA Secondary Structure on Elongation and Fidelity.

摘要

Secondary DNA structure or DNA damage within transcription units can interfere with RNA polymerase elongation and alter transcript production and integrity. In some cases, damage to DNA within transcription units can signal transcription-coupled DNA repair, a genomic maintenance pathway that removes DNA damage from the genome, likely in response to RNA polymerase stalling at the lesion. In the work reported here, observations related to transcription-coupled DNA repair and alterations to transcript integrity were extended in two ways. First, DNA secondary structure in the form of stem loops and unpaired loops was shown to impede or block RNA polymerase II transcription, but these structural elements did not induce transcription-coupled DNA repair or any repair pathway to remove them. These results support a model for transcription-coupled DNA repair in which a block to transcription might be necessary to signal the pathway's operation, but it is not sufficient to induce removal of DNA unless damage is present as well. Second, studies were done to determine if DNA damage in a transcription unit that does not block RNA polymerase progression can directly alter full-length mRNA in way that could change the primary structure of proteins following translation. O6-Methylguanine, a lesion in DNA that does not block RNA polymerase II, was shown to induce modifications to mRNA during transcription, resulting in changes to protein structure following translation of the aberrant RNA. This work has implications in the etiology of certain diseases, including the autosomal dominant Huntington's disease, as well as cancer and cancer therapy.