Researchers at the Salk Institute have discovered an on/off switch for telomerase, an enzyme that rebuilds a cellular timekeeper known as a telomere. The scientists believe that the discovery could provide a way to get human cells to divide indefinitely without degenerating, thereby regenerating healthy organs even in old age.

Telomeres, which can be likened to caps at the end of chromosomes that protect against deterioration, shorten as we age. Once they are too short for the cell to divide, organs and tissues degenerate. Telemorase has been the focus on many aging-related research efforts due to its ability to rebuild these telomeres and allow cells to divide indefinitely.

"Previous studies had suggested that once assembled, telomerase is available whenever it is needed," says Vicki Lundblad, professor and holder of Salk’s Ralph S. and Becky O'Connor Chair. "We were surprised to discover instead that telomerase has what is in essence an 'off' switch, whereby it disassembles."

The researchers say that finding a way to control this "off" switch could provide a way to slow down the telomere-shortening process, leading to treatments for age-related diseases and the ability to regenerate organs later in life.

Study senior author Lundblad and graduate student Timothy Tucey made the discovery in the yeast Saccharomyes cerevisiae. This is the same yeast used to make wine and bread and has previously been the subject of study by Lunblad's group aimed at laying the groundwork for guiding similar findings in human cells.

By developing a technique that allowed each component during cell growth and division – which involves the duplication of the entire genome – to be observed at very high resolution, the team was able to gain an understanding of how telomerase assembles.

They discovered that every time a cell divides, telomerase, minus a critical molecular subunit, sits ready to spring into action. When the genome has been fully duplicated, the missing subunit joins the party to form a complete, fully active telomerase complex that can replenish the ends of eroding chromosomes to ensure robust cell division.

To their surprise, Tucey and Lundblad discovered that immediately after the full telomerase complex has been assembled, it quickly disassembles to form an inactive "disassembly" complex. In other words, the switch is essentially flipped to the "off" position. They hypothesize that this may take place to keep telomerase at exceptionally low levels inside the cell.

While manipulating this on/off switch has the potential to encourage healthy cells to keep dividing and generating in old age, the opposite is also true. Because cancer cells rely on elevated telomerase levels to ensure unregulated cell growth, manipulating the "off" switch could help keep telomerase activity below that point.

The team's study appears in the journal Genes and Development.

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