A Tale of Raggedy Endy
Authors: Beckman Mary 
Published: August 2003

A mechanic doesn't wield a Phillips screwdriver when she should be using a flathead, and yeast seem to be just as discerning when repairing their DNA. New research shows that withering chromosomes spur these microbes to crank up a DNA damage response that's customized with a dozen dedicated genes. The work reveals that chromosome extremities might do more than passively protect genes. It also raises the possibility that yeast might help ferment theories about how chromosome tip integrity contributes to human cell aging.

The design of a cell's DNA-copying machinery prevents it from replicating chromosome ends. Left unattended, DNA molecules would shorten every time a cell divides. Long stretches of repeated DNA sequences called telomeres buffer chromosome ends to some extent, absorbing the shrinkage of each replication. As the telomeres in human cells shrivel, the cells stop growing and enter a state called senescence, which is metabolically distinct from both dying and actively dividing cells and might contribute to organismal aging (see
"More Than a Sum of Our Cells"
).

In the yeast
Saccharomyces cerevisiae
, an enzyme called telomerase replenishes chromosome ends. Nautiyal and colleagues probed how
S. cerevisiae
would cope with receding telomeres by engineering a strain that lacks telomerase. The majority of the organisms lost between 50% and 75% of their telomeres after 5 days in culture and reproduced increasingly sluggishly until they stopped.

To find out how telomerase loss influences gene expression, the researchers used microarrays to measure the amount of every messenger RNA in telomerase-deficient yeast. Of the organism's approximately 6200 genes, 650 shifted into high or low gear compared with those in unmodified yeast, suggesting that a wide-ranging cellular response kicks in as telomeres disappear. Some of the activated genes are known to help the cell counter DNA damage. By reviewing studies on normal yeast subjected to different types of DNA assaults, the researchers pared down the 650 genes to 12 that are unique to telomerase-deficient cells. Only two had previously been associated with telomeres, and four had had no known function. The team proposes that the cell uses these 12 genes to modify its usual reaction to DNA injury.

The data show that cells view dwindling telomeres as a type of damaged DNA, says cell biologist Judith Campisi of Lawrence Berkeley National Laboratory in California. "This was suspected, but the data were scant," she says. The findings support the idea that telomeres exist so that chromosome ends won't be treated as broken DNA, but the implications of the new work don't stop there. The observation that telomere loss alters the activity of a specific set of genes in addition to those involved in DNA repair suggests that "telomeres ensure proper gene regulation and that this regulation is lost when telomeres malfunction," says Campisi. Although yeast and human telomere biology differ, biochemist Kathleen Collins of the University of California, Berkeley, speculates that the newly discovered response is similar to what happens as human cells senesce. If so, yeast might lead the way to candidate senescence genes in human cells, perhaps providing the means to learn about human ends.

--Mary Beckman

J. S. Nautiyal, J. L. DeRisi, E. H. Blackburn, The genome-wide expression response to telomerase deletion in
Saccharomyces cerevisiae
.
Proc. Natl. Acad. Sci. U.S.A.
, 25 June 2002 [e-pub ahead of print].
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