Sci. Aging Knowl. Environ., 19 March 2003
Decorated for Death
Tagging DNA-silencing protein trims survival in high-living yeast
Key Words: silent-mating-type cassette telomere mitogen-activated protein kinase NetPhos
In good times, yeast grow fast and breed furiously but only for a short time. If conditions turn grim, cells become abstemious and last longer. When yeast cells choose the prodigal lifestyle, they slap chemical tags onto a gene-silencing protein. This alteration slashes longevity, according to new research. The study, the first to link aging to modification of the DNA on-off switch, raises the question of how the protein interacts with a related one that lengthens life.
The protein Sir2p silences, or shuts down, genes, thwarts DNA shuffling, and is a powerful tonic for yeast. Hiking its output boosts by 40% the number of times a cell can produce offspring--a measure of longevity in yeast. One way that Sir2p prolongs life is by blocking production of harmful DNA loops that stack up in aging yeast. Previous work intimated that Sir3p, a silencing protein that resembles Sir2p, also regulates longevity. Cells intent on growing quickly and procreating activate a pathway that involves a protein called Slt2p, which prepares the cell for duplication by awakening genes that advance the yeast through its division cycle and rebuild its wall. The same cells also show Sir3p studded with extra phosphate groups. Together, these findings suggested that the Slt2 pathway governs longevity by controlling the number of phosphate groups glued to Sir3p.
To test this hypothesis, Ray and colleagues manipulated the degree of Sir3p phosphorylation. They found that phosphates glommed onto four serines--amino acids--in Sir3p. The researchers changed them to alanines, which can't grip phosphate, and gave the altered cells plenty to eat--thus rousing the Slt2 pathway. Yeast carrying serine-stripped Sir3p outlived normal cells by 24%. The scientists conclude that the Slt2-controlled phosphorylation of Sir3p truncates life span. The findings expose part of the mechanism that allows yeast to live lavishly when the environment is benign, says co-author Kurt Runge, a yeast molecular biologist at the Cleveland Clinic Foundation in Ohio. Unlike Sir2p, Sir3p doesn't stretch longevity by blocking the formation of DNA circles: Long-lived cells with serine-free Sir3p showed no fewer DNA circles than did shorter-lived normal cells. It's possible, however, that the protein silences the genes on the circles, which could conceivably lengthen life, Runge says.
That Sir3p seems to regulate life span in a different manner than Sir2p does creates an interesting puzzle, says cell biologist David Sinclair of Harvard Medical School in Boston. "We need to figure out what phosphorylated Sir3 does to the cell to shorten life span," he says. However, he's concerned that even the unadulterated yeast in the experiment have abnormally short lives and that stripping phosphates from Sir3p merely restores normal life span instead of adding time. The pathway incorporating Sir2p responds to hunger, and the one involving Sir3p responds to stresses such as heat, says molecular geneticist John Aris of the University of Florida in Gainesville. So a key question, he says, is how the pathways "cooperate with and antagonize each other in regulating life span." That answer might tell us how living it up cuts life short.
--Mitch Leslie; suggested by Greg Liszt
March 19, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150