Dynamics of Transcription Coupled Repair

Cornell University, Ithaca NY

Investigators

Abstract

UV damage to DNA affects the world population, resulting in sunburn, cataracts, weakened immune systems, skin cancer and lower food production, and thus, detailed insight into how this damage is recognized and repaired may present novel targets for future intervention, particularly in relation to cancer and ageing. This type of DNA damage is disruptive to both DNA replication and transcription (the process of gene expression) and must be repaired in a timely fashion to ensure proper cell function and viability. Transcription coupled repair (TCR) is part of a global DNA repair mechanism and efficiently targets DNA damage that interferes with transcription. This project will provide a comprehensive understanding of the role that the bacterial transcription coupling factor, Mfd, plays in TCR by detecting, tracking, and visualizing relevant molecular events during the repair process. The project will offer research training opportunities to students, and the topic presents accessible educational opportunities concerning sun exposure, damage and protection for a general audience. An educational module, covering topics such as sunburn, DNA repair and long term skin damage, will be developed to bring public awareness to UV-exposure and it will accessible to teachers nationwide via the "Lending Library" of the Cornell Center for Materials Research. The complexity of eukaryotic TCR impedes detailed molecular investigation; therefore, bacterial TCR, which shares many characteristics, can serve as a simpler model system. This research is aimed at answering a number of unresolved kinetic and mechanical questions concerning TCR, specifically how Mfd and UvrAB proteins that initiate nucleotide excision repair (NER) are targeted to a lesion and the broader differential functions of Mfd. The research group has an established track record for developing novel single molecule methods to address fundamental questions in transcription and DNA replication. Utilization of new techniques based on DNA unzipping will allow direct resolution of critical molecular events in TCR, and complement existing biochemical and structural studies, ultimately enabling a more comprehensive view of the timing and interactions essential to TCR. An in-depth understanding of the relationships among relevant proteins in TCR-NER could give us a broader understanding of bacterial TCR-NER and, potentially, transcription overall. Additionally, further elucidation of the function and roles of bacterial proteins could shed significant light on TCR-NER eukaryotic counterparts, providing essential information and enabling clarification of a more complex system. The results of this work will significantly contribute to our understanding of the mechanism of TCR by providing unprecedented views of a fundamental biological process.