Telomerase, an enzyme that essentially adds time to the chromosome’s countdown clock, was once thought to carry out its life-sustaining duties whenever it happened to be present. That is, telomerase was thought to be “on” always, lengthening telomeres, the protective tips of chromosomes. By lengthening telomeres, which erode just a bit with each round of cell division, telomerase allows cells to divide indefinitely, ensuring that a constant supply of fresh, healthy cells keeps replenishing vital tissues.

The only problem, it was thought, would be a lack of telomerase; however, it turns out that telomerase activity is a little more complicated.

Telomerase, say researchers at the Salk Institute, has a kind of on/off switch. And if the switch happens to be flipped to the “off” position, merely having adequate telomerase levels in the cells is, well, inadequate.

This finding emerged from work led by Vicki Lundblad, professor and holder of Salk’s Ralph S. and Becky O’Connor Chair. Dr. Lundblad, together with graduate student Timothy M. Tucey, studied how telomerase worked in the yeast Saccharomyces cerevisiae. Previously, Dr. Lundblad’s group used this simple single-celled organism to reveal numerous insights about telomerase and lay the groundwork for guiding similar findings in human cells.

“We wanted to be able to study each component of the telomerase complex but that turned out to not be a simple task,” Tucey said. Tucey developed a strategy that allowed him to observe each component during cell growth and division at very high resolution, leading to an unanticipated set of discoveries into how—and when—this telomere-dedicated machine puts itself together.

These discoveries appeared September 19 in the journal Genes and Development, in an article entitled, “Regulated assembly and disassembly of the yeast telomerase quaternary complex.” The discoveries encompassed interactions involving the various telomerase complex components, which include the catalytic Est2 protein and two regulatory subunits (Est1 and Est3) in association with the TLC1 RNA.

“A hierarchy of assembly and disassembly results in limiting amounts of the quaternary complex late in the cell cycle, following completion of DNA replication,” wrote the authors. “The assembly pathway, which is driven by interaction of the Est3 telomerase subunit with a previously formed Est1–TLC1–Est2 preassembly complex, is highly regulated, involving Est3-binding sites on both Est2 and Est1 as well as an interface on Est3 itself that functions as a toggle switch.”

While cell division is in progress, the telomerase complex idles in a kind of “preassembly” mode, minus a particular subunit. Then, once division is complete, when the genome has been fully duplicated, the telomerase complex acquires the missing subunit and becomes fully active. Yet, immediately after it has been assembled, the complete telomerase complex rapidly disassembles.

“The balance between the assembly and disassembly pathways, which dictate the levels of the active holoenzyme in the cell, reveals a novel mechanism by which telomerase (and hence telomere homeostasis) is regulated,” the authors explained.

The authors speculated that this disassembly pathway may provide a means of keeping telomerase at exceptionally low levels inside the cell. Although eroding telomeres in normal cells can contribute to the aging process, cancer cells, in contrast, rely on elevated telomerase levels to ensure unregulated cell growth. The “off” switch discovered by Tucey and Lundblad may help keep telomerase activity below this threshold.

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