Susan M. Rosenberg, Ph. D.
Ben F. Love Chair in Cancer Research
Department of Molecular and Human Genetics
Department of Biochemistry and Molecular Biology
Department of Microbiology and Immunology
- Ph.D., University of Oregon, 1986
- Postdoctoral, 1987-1988, University of Paris
- Postdoctoral, 1988-1989, University of Utah
Molecular Mechanisms of Genetic and Genomic Change and DNA Repair
Stationary-Phase Mutation in Escherichia coli
For 50 years, the world believed that mutations occur at random. The discovery of "adaptive mutation" in bacteria shook the foundation of that dogma, implying the existence of a another kind of mutation that differs from normal spontaneous mutations. The "adaptive" mutations occur when they are selected, in cells that appear not to be dividing, and had been found only in genes whose functions were selected. We are elucidating the molecular mechanism by which these mutations form. We have found that genetic recombination enzymes are required for some adaptive mutations. We are uncovering a new and unexpected molecular mechanism for mutation in nondividing cells that includes DNA double-strand breaks, recombination, DNA synthesis, and suspension of postsynthesis mismatch repair, and which occurs in a hypermutable subpopulation of the cells. The mutations are similar to those characteristic of some cancer cells. This new mutation mechanism in nondividing cells may be an important model for mutations that give rise to some types of cancer and genetic diseases, cause resistance to chemotherapeutic and antibiotic drugs, lead to pathogenicity of microbes, and participate in many other systems previously thought to follow the rules of classical growth-dependent mutation.
Mechanism and Regulation of Mismatch Repair
The most important cellular system for preserving genetic stability in organisms from eubacteria to humans is mismatch repair (MMR). MMR corrects replication errors and inhibits genome rearrangements and horizontal gene transfer. We have discovered that this system is down-regulated in stressed starved E. coli. We are studying both its molecular mechanism and regulation in vivo in E. coli.
In collaboration with Dr. Joel Weiner's group at the University of Alberta, we have discovered that some mutations that confer antibiotic resistance are formed by a mechanism that is similar to the recombination-dependent stationary-phase (adaptive) mutation described above. We are examining the mechanism by which these mutations form.
DNA Double-Strand Break-Repair Recombination
DNA recombination is one of the primary ways that genomes change and is an important tool for gene targeting in gene therapy. We want to understand how such recombination works. Chi sites (5'GCTGGTGG) are hot spots for recombination in E. coli. Chi is recognized by the recombination enzyme RecBCD, which works in a pathway with RecA and other proteins to recombine homologous DNAs. Chi and RecBCD facilitate a rate-limiting step in recombination. We want to know how that step works and how the proteins recombine the DNA. We suggested an unusual model for the molecular mechanism of recombination. To test our model, we are probing the structures of the DNA intermediates of recombination in vivo, characterizing the structures of the finished recombination products, and finding new proteins that affect recombination. We have discovered that recombination induces DNA replication. We are studying this process.
Regulation of Recombination in Cancer and Development
Genomic instability is a hallmark of cancer in which translocations and other gross rearrangements are seen. We are testing the hypothesis that rearrangements in cancer result from a decrease in the stringency of homologous recombination, letting sequences with only partial similarity recombine. We suggested that loss of recombination stringency might also occur at a stage in normal development of the immune system. We are using transgenic mice with special recombination substrates in their genomes to investigate this possibility.