Human Genome Stability, DNA Damage Response, HIV Replication & Evolution
Our group began in 1977 with a research interest in the mechanisms of chromosomal DNA replication. We defined the biochemical functions of proteins in the human replication system. The proteins in this complex display unique mechanisms of protein-DNA interaction. Specifically, many of them associate with PCNA, a toroidal sliding clamp protein that facilitates movement and coordinated action of the other proteins. Some proteins in the complex have tracking mechanisms of their own. An example is the flap endonuclease that enters a DNA strand from the 5' end and then moves to the point of cleavage.
June 19, 2007
David S. Guzick, M.D., Ph.D., Dean of the University of Rochester's School of Medicine and Dentistry, wrote in his recent Dean's Newsletter that,
A truly great scientific career is measured not only by the direct impact of the scientist's original work, but by the impact on the field of his or her progeny--students mentored by the scientist who go on to make substantial contributions themselves.
It is, therefore, truly wonderful to share with you our excitement for Bob Bambara, Ph.D., Professor and Chair of the Department of Biochemistry and Biophysics, who was honored at the University's May 19 Commencement Exercises with the William H. Riker University Award for Excellence in Graduate Teaching, continued Guzick.
This is the first Riker award to go to a faculty member at the medical school. The Riker Award is also for mentoring students who go on to have successful careers. That being said, Bob's students are professors at the University of California, Indiana, Kentucky, Leiden, North Carolina, and Virginia. Two are Professors at the University of Rochester, and two are Deans! Others head large biochemistry programs in biotech, and one is vice president of a major company.
Maintenance of genome stability is a top priority of human cells. This process slows aging and suppresses carcinogenesis. One mechanism is a signaling pathway that recognizes when chromosomal DNA has been damaged, and stops DNA replication to allow for DNA repair. A major repair pathway, base excision repair, employs mostly the same enzymes as the replication system. How does the cell disconnect these enzymes from replication and reassemble them for repair? Current work suggests that they are dissociated from the PCNA and reassembled around a repair nuclease and coordination protein called APE.
Another area of work in our laboratory is analysis of the steps of HIV DNA replication and recombination. The replication mechanisms of the virus differ from those of the host cell in many ways. We are particularly interested in understanding those differences, since they provide sites for therapeutic interference with viral replication by means that do not disrupt human cellular function. We have also investigated the mechanism by which human steroid receptors regulate gene expression. This project has entered an engineering phase in which we can introduce structurally modified receptors into cells to regulate the expression specific genes. This technology is a novel approach to potential anti-tumor therapy.
- The 9-1-1 checkpoint clamp stimulates DNA resection by Dna2-Sgs1 and Exo1. Nucleic Acids Res. In press. (2014 Aug 13).
- GTP is the primary activator of the anti-HIV restriction factor SAMHD1. J Biol Chem. 289, 16641. (2014 Jun 13).
- Anti-HIV host factor SAMHD1 regulates viral sensitivity to nucleoside reverse transcriptase inhibitors via modulation of cellular deoxyribonucleoside triphosphate (dNTP) levels. J Biol Chem. 289, 16640. (2014 Jun 13).