Edward H. Egelman, PhD
Recombination and DNA repair (Genomic instability and cancer)
Research in the Egelman lab is focused is on the structure and function of macromolecular complexes, mainly using the tools of electron microscopy and image analysis. In particular, protein-DNA complexes active in homologous recombination (such as those formed by bacterial RecA protein and the human RAD51 protein), DNA helicases, and actin have been studied for many years. While homologous recombination generates genetic diversity, and thus improves the fitness of a population, it appears that it also is an important mechanism in the cell for the repair of DNA. Breakdowns in this repair machinery have been clearly tied to cancer, and thus the understanding of how human proteins such as RAD51 work is of fundamental importance to understanding normal and pathological repair of DNA damage. The role of DNA recombination in cancer has been highlighted by the fact that the BRCA2 protein, whose mutations lead to familial breast cancer, interacts with RAD51 and targets it to the sites of DNA damage.
Most of the 12 helicases in E. coli are not essential genes, and they are still trying to understand the role played by these proteins. The situation is more complex in eukaryotes, since it now appears that there are at least 137 different helicases encoded by the S. cerevisiae genome, indicating that ~2% of the genes in yeast encode helicases. The importance of helicases in humans has been boosted by several very dramatic findings. A bizarre hereditary disorder, Werner's Syndrome, in which aging is grossly accelerated (and where death frequently occurs from cancer) has been shown to be due to a mutation in a gene encoding a helicase. Another human disorder, Bloom's Syndrome, with elevated levels of cancer, has been shown to be due to a mutation in another helicase. This helicase is a homolog of the E. coli RecQ protein. Structural studies of helicases will thus be an important element not only in understanding DNA replication, where helicases were first identified, but in understanding the control of genome stability and cancer in humans.
Actin is one of the most abundant eukaryotic proteins. While first studied in muscle, they now understand that actin is crucial to the control of cell shape and motility in all human cells. In particular, changes in the actin cytoskeleton are an important element in cell migration during metastasis of cancer cells. In collaboration with the Parsons lab, studies are in progress to look at the interaction of cortactin with actin filaments.