Molecular machinery of the bacterial nucleotide excision repair pathway

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The goal of this project is to understand how cells repair damaged DNA. The process of DNA repair is essential to ensure that the genetic information in the DNA genome remains intact. Inside cells, DNA is continually under assault from multiple sources, including its watery environment, chemicals produced by metabolism, or exposure to external radiation or toxins. To protect the DNA, cells have evolved biochemical processes that patrol the genome, detect damage, and organize responses aimed at restoring the integrity of the DNA. This project focuses on one such repair process, called nucleotide excision repair, in which damaged segments of DNA are removed and replaced with normal DNA. This work will be carried out in bacteria, but because DNA repair mechanisms are similar in higher organisms, including humans, the results should have wide-ranging scientific impact. The project also will have educational impact through programs for engaging undergraduates in research and creative arts and for outreach to public schools in New York City. These educational activities will help fulfill two broad missions: for scientists to attract and retain students in science, technology, engineering, and mathematics (STEM) fields, and for the City College of New York to provide a high-quality and affordable education to children of New York City, immigrants, minorities, and those without economic means. DNA repair is a fundamental process dedicated to maintenance of genetic information, yet many mechanistic details of DNA repair remain obscure. This research will fill gaps in our understanding of one DNA repair pathway, bacterial nucleotide excision repair. Previous research established roles for three proteins, UvrA, UvrB, and UvrC, which function via a series of large and dynamic multi-protein complexes. By applying biochemical, biophysical, and structural approaches, experiments will test structure-based models for three mechanisms: 1) identification of damaged DNA from a background of native DNA, 2) nucleotide binding and hydrolysis, and 3) the molecular choreography of UvrA and UvrB on lesion-containing DNA. The results are expected to provide new insights into how nucleotide excision repair occurs in the context of genome surveillance and repair. Moreover, this knowledge will influence our views of other cellular activities, including DNA replication, gene expression, evolutionary processes and the cellular processes of apoptosis, senescence, and tumorigenesis.This award is co-funded by the Genetic Mechanisms and the Molecular Biophysics programs in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.