Following his 2003 landmark discovery in yeast that shed light on why age is the greatest cancer risk factor in humans, Dr. Dan Gottschling and colleagues have zeroed in on a key underlying cellular process that goes awry with age.
Their findings, “Mitochondrial Dysfunction Leads to Nuclear Genome Instability via an Iron-Sulfur Cluster Defect,” appeared in the June 26 issue of Cell.
Nearly 80 percent of cancers are diagnosed in people over 55. Curious about this biological phenomenon, Gottschling has worked to understand one of the hallmarks of cancer: genome instability—or unstable DNA—as a function of age. Yeast provides an analogous model organism because it, too, exhibits genetic instability in middle and late life.
The new finding reveals that unstable DNA in the nucleus of the cell is linked to iron-sulfur cluster (ISC) biogenesis, a process required by a number of cellular proteins for structural integrity and normal enzyme activity.
As yeast cells age, some processes in the mitochondria—the power plants of a cell—no longer work properly. Key among these, the researchers found, is a defect in ISC biogenesis. This in turn inhibits production of ISC-containing proteins that are required for integrity of the nuclear genome.
Gottschling said this age-related process in yeast relates to human cancer in two ways. “First, all of the processes and many of the molecules found in our study turn out to be conserved from yeast to humans. Second, in our analysis of yeast, we did it under fermentative growth, which is analogous to a metabolic process in human tumors—the ‘Warburg effect.’ As a consequence of this metabolic state, the tumor cells may have more chances to change genetically and become more aggressive or invasive.”
Co-authors of the study were Zara Nelson, research technician in the Gottschling Lab, and two former graduate students in the lab: Dr. Joshua Veatch, who is completing his medical training in the Hutchinson Center/University of Washington M.D./Ph.D. program, and Dr. Michael McMurray, who is a postdoctoral fellow at the University of California at Berkeley.
To read about the Gottschling Lab’s 2003 discovery in Center News, click here.