Like a homeowner who finds it hard to put down the hammer and saw, living creatures from yeast to man can't resist tinkering with the structure of their chromosomes. But this cellular remodeling job isn't simply to brighten up appearances: Without careful organization of its chromosomes' three-dimensional bulges and twists, an organism may be unable to control the action of its genes — which may lead to death or diseases like cancer.
Understanding how cells accomplish this complex remodeling project is the research focus of Tom Fazzio, one of this year's Harold M. Weintraub Graduate Student Award winners and a Molecular and Cellular Biology graduate student. Fazzio is completing his doctoral work in Dr. Toshi Tsukiyama's lab in the Basic Sciences Division.
Fazzio and his colleagues in the Tsukiyama lab study chromatin, made up of a chromosome's string-like DNA wrapped around bead-like protein structures called nucleosomes, which serve as a kind of scaffold that helps give a chromosome its defined shape. The scaffolding is carefully built in such a way to ensure that genes can be turned on or off in response to environmental cues or at different times in development.
"The lab is interested in chromatin structure because it imparts some level of regulation on all cell processes that involve DNA," Fazzio said. "This includes gene regulation — the process by which genes are activated or repressed — as well as DNA duplication and segregation (pulling apart) of duplicated chromosomes prior to cell division. Any perturbation in any of these events can cause problems." For example, cancer cells have multiple misregulated genes and also frequently have defects in correctly partitioning their chromosomes between newly divided cells.
Fazzio studies a set of proteins in yeast called ISWI chromatin-remodeling factors, which have counterparts in many other organisms including humans. He's found that the ISW1 complex actually slides nucleosomes along the DNA to position them to specific parts of genes, where they block the genes from being activated inappropriately. The findings were published last November in Molecular Cell.
The study of this phenomenon and related aspects of chromatin remodeling is critical to the understanding of gene regulation, Fazzio said. "The more we understand how gene expression is regulated, the better equipped we'll be to develop ways to counteract abnormal gene expression that can lead to disease."
Fazzio will defend his thesis May 13. This summer, he will begin postdoctoral studies with Dr. Barbara Panning at the University of California, San Francisco to continue studies of chromatin structure in mice.
When Michael McMurray began graduate school in 1997, he knew it would take dedication and perseverance. Those qualities were instrumental in McMurray's discovery last year that simple baker's yeast show striking similarities to humans with regard to the changes their genes undergo as they age, an accomplishment that earned him a 2004 Harold M. Weintraub Graduate Student Award. The study — which began as just a back-burner project — required him to spend days at a time camped out in Dr. Dan Gottschling's Basic Sciences Division lab, where McMurray painstakingly separated dividing yeast cells from one another to monitor their lifespan.
When yeast cells hit the equivalent of late-middle age, McMurray found that they experience a sudden, 200-fold surge in the production of genetic changes known as loss of heterozygosity, or LOH, a condition characterized by missing or mutated chromosomes that is frequently associated with cancer. This finding suggests that the yeast Saccharomyces cerevisiae, a simple, single-celled organism, may be an ideal model for understanding the complexities of age-related cancer development in humans. The findings were published last September in Science.
"At first it was a shot in the dark to see if we'd see anything by doing things this way," said McMurray of the grueling experiments. "But then a series of little observations made during those painful experiments kept intriguing me, suggesting maybe something important was going on."
McMurray's discovery that an age-dependent switch is somehow activated to trigger genomic instability could have major scientific consequences, potentially enabling scientists to understand the causal event at the onset of cancer development.
McMurray expects to defend his thesis this spring. Next fall, he will begin postdoctoral work in Dr. Jeremy Thorner's lab at the University of California, Berkeley, where he will study how yeast cells correctly position the septin ring, the structure that determines where a growing cell pinches into two daughter cells during cell division. After learning what a powerful system yeast can be for revealing answers to important biological problems, "it's very hard to imagine leaving it now," McMurray said.