December 19, 2013
Just like the chicken or milk you buy at a store, chromosomes have a shelf life too. Of course, chromosomes don’t spoil because of growing bacteria. Instead, they go bad because they lose a little of the telomeres at their ends each time they are copied. Once these telomeres get too short, the chromosome stops working and the cell dies.
Turns out food and chromosomes have another thing in common—the rates of spoilage of both can be affected by their environment. For example, we all know that chicken will last longer if you store it in a refrigerator and that it will go bad sooner if you leave it out on the counter on a hot day. In a new study out in PLoS Genetics, Romano and coworkers show a variety of ways that the loss of telomeres can be slowed down or sped up in the yeast S. cerevisiae. And importantly, they also show that some forms of environmental stress have no effect.
The authors looked at the effect of thirteen different environments on telomere length over 100-400 generations. They found that caffeine, high temperature and low levels of hydroxyurea lead to shortened telomeres, while alcohol and acetic acid lead to longer telomeres. It seems that for a long life, yeast should lay off the espresso and and try to avoid fevers, while enjoying those martinis and sauerbraten.
Romano and coworkers also found a number of conditions that had no effect on telomere length, with the most significant being oxidative stress. In contrast, previous studies in humans had suggested that the oxidative stress associated with emotional stress contributed to increased telomere loss; given these results, this may need to be looked at again. In any event, yeast can deal with the stresses of modern life with little or no impact on their telomere length.
The authors next set out to identify the genes that are impacted by these stressors. They focused on four different conditions—two that led to decreased telomere length, high temperature and caffeine, one that led to longer telomeres, ethanol, and one that had no effect, hydrogen peroxide. As a first step they identified key genes by comparing genome-wide transcript levels under each condition. They then went on to look at the effect of each stressor on strains deleted for each of the genes they identified.
Not surprisingly, the most important genes were those involved with the enzyme telomerase. This enzyme is responsible for adding to the telomeres at the ends of chromosomes. Without something like this, eukaryotes, with their linear chromosomes, would have disappeared long ago.
A key gene they identified was RIF1, encoding a negative regulator of telomerase. Deleting this gene led to decreased effects of ethanol and caffeine, suggesting that this gene is key to each stressor’s effects. The same was not true of high temperature—the strain deleted for RIF1 responded normally to high temperature. So high temperature works through a different mechanism.
Digging deeper into this pathway, Romano and coworkers found that Rap1p was the central player in ethanol’s ability to lengthen telomeres. This makes sense, as the ability of Rif1p to negatively regulate telomerase depends upon its interaction with Rap1p.
Caffeine, like ethanol, affected telomere length through Rif1p-Rap1p but with an opposite effect. As caffeine is known to be an inhibitor of phosphatydylinositol-3 kinase related kinases, the authors looked at whether known kinases in the telomerase pathway were involved in caffeine-dependent telomere shortening. They found that when they deleted both TEL1 and MEC1, caffeine no longer affected telomere length.
The authors were not so lucky in their attempts to tease out the mechanism of the ability of high temperature to shorten telomeres. They were not able to identify any single deletions that eliminated this effect of high temperature.
Whatever the mechanisms, the results presented in this study are important for a couple of different reasons. First off, they obviously teach us more about how telomere length is maintained. But this is more than a dry, academic finding.
Given that many of the 400 or so genes involved in maintaining telomere length are evolutionarily conserved, these results may also translate to humans too. This matters because telomere length is involved in a number of diseases and aging.
Studies like this may help us identify novel genes to target in diseases like cancer. And they may help us better understand how lifestyle choices can affect your telomeres and so your health. So if you have a cup of coffee, be sure to spike it with alcohol!
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics
Categories: Research Spotlight