Jeffrey S. Smith, PhD
Chromatin modifications, silencing, aging and apoptosis
The Smith lab utilizes molecular genetics of the budding yeast, Saccharomyces cerevisiae, to dissect the molecular mechanism of transcriptional silencing at telomeres and the ribosomal DNA (rDNA). Silencing is dependent on the deacetylation of histones by Sir2, which is the founding member of a phylogenetically conserved family of NAD+-dependent protein deacetylases called the sirtuins. In addition to transcriptional silencing, the sirtuins of higher eukaryotes have been implicated in the regulation of multiple cellular processes, including development, stress response, aging, and apoptosis. For example, the human SIRT1 protein deacetylates p53 and NF-?B to inhibit or promote apoptosis, respectively, depending on the specific cellular signal. The lab has discovered two critical roles for the NAD salvage pathway in yeast cells that regulate the aging and silencing functions of Sir2. The first is maintenance of high intracellular NAD+ concentrations, and the second is limiting the concentration of nicotinamide, a byproduct of the Sir2-mediated deacetylation reaction, which is also a strong non-competitive Sir2 inhibitor. This research made use of the DNA core facility for DNA sequencing. The lab is now collaborating with the Marty Mayo's lab (also in the Biochemistry and Molecular Genetics Dept.) to investigate whether SIRT1-mediated deacetylation of NF-kB and the promotion of apotosis in non-small cell lung cancer cells is regulated by NAD biosynthesis pathways. In a project related to Sir2 and NAD+ biosynthesis, the lab has recently been investigating the role of these factors in longevity, again using yeast cells as a model system. The project involves studying how Sir2 and the NAD salvage pathway function in the extension of longevity caused by caloric restriction, a dietary regimen that is known to also prevent cancer in mice.
The lab collaborates with Ann Beyer's lab to investigate the role that chromatin structure plays in the repression of rDNA transcription mediated by RNA polymerase I. This project is relevant to cancer because one of the hallmarks of tumor cells is an enlargement of the nucleolus. The enlarged nucleoli are due, in part, to a marked elevation in rDNA transcription. It is therefore critical to understand the normal repressive mechanism.