Size matters: Shortest telomeres initiate cellular havoc

October 04, 2001

Using genetically engineered mice, scientists from The Johns Hopkins University School of Medicine have found that events associated with losing the function of telomeres, the repetitive ends of chromosomes, depend on the length of the shortest telomere in a cell, not the commonly measured average length.

Without telomere function, a cell's chromosomes can rearrange, scrambling their genetic information, halting cell division and eventually leading to the cell's death. Understanding the details of telomere function and its connection to cellular death may eventually provide targets for treating cancer, says Carol Greider, Ph.D.

"Rather than average telomere length, it's the shortest telomere length that makes the biggest difference to a cell," explains Greider, a professor in the Department of Molecular Biology and Genetics, part of the school's Institute for Basic Biomedical Sciences. "This is a fundamental change in the way that most scientists think about telomere length."

Building on their discovery, the researchers found that turning on telomerase, the enzyme that rebuilds telomeres, lengthens the shortest telomeres just enough to restore function, without significantly increasing average length. A report of the study, funded by the National Institutes of Health, appears in the Oct. 5 issue of the journal Cell.

Telomeres cap the chromosome ends, protecting the interior, gene-containing parts of the chromosome from being accidentally lost. In most normal cells, the telomeres shorten each time a cell divides, eventually preventing cell division. Cancer cells, however, can divide almost indefinitely because telomerase is turned on. The cells that give rise to sperm and egg also have telomerase to maintain genome integrity in subsequent generations.

Most studies have relied on a general measure of telomeres' integrity -- the decreasing average length of telomeres in a group of cells -- as the harbinger of telomere dysfunction. But two studies from Greider's lab now show the actual signal to the cell to be a critically short telomere. Says Greider, "To fully understand the role of telomeres in cancer, we wanted to know what precisely signals the cell to arrest or die."

In an earlier study using yeast, graduate students Jennifer Hackett and David Feldser proved that losing telomere function directly caused the organism's genome to become unstable, accumulating genetic and chromosomal changes. Turning on telomerase prevented this instability, they reported in the Aug. 10 issue of Cell.

In the newest study, lead author Michael Hemann and others in Greider's lab examined individual telomere length in genetically engineered mice to show exactly what triggers the instability and how telomerase prevents it.

In mice without functional telomerase, so-called "telomerase-null" mice, each generation has a shorter average telomere length, and by roughly the sixth generation, a few chromosome ends have extremely short telomeres, says Hemann. Which chromosomes have the shortest telomeres depends only on telomere length in the original parent mice, adds Greider.

To determine whether average length or extreme short length was the key trigger, the scientists bred the null mice (with short telomeres) to mice that have one telomerase gene turned on in all their cells (giving them long telomeres).

This breeding creates two types of hybrid mice whose average telomere length falls between those of the parents. Both types of offspring inherit half short telomeres and half long telomeres, since one copy of each chromosome is inherited from each parent. However, one quarter of the offspring mice also inherit a working gene for telomerase to rebuild their telomeres.

Close examination of cells from the hybrid offspring lacking telomerase showed that chromosome rearrangements began when one or two chromosomes' telomeres were all but gone. During cell division the shortest-telomere chromosome frequently fused with its own copy or with a second chromosome with short telomeres.

"Our evidence suggests that once a telomere becomes very short, the cell recognizes it as a DNA break," explains Greider. "Broken DNA commonly signals normal cells to arrest or die as a protection against chromosome rearrangement and cancer."

In addition to chromosome changes, the scientists also examined the extent of cell death, particularly in testes. Despite having an average telomere length in between that of their parents, the telomerase-null offspring exhibited cell death clearly in line with the short-telomere parent.

"These mice showed cell death equivalent to the short-telomere parent, rather than the level expected if the average telomere length was the signal," says Greider. "However, we also saw that telomerase was able to rescue that characteristic in the offspring."

The hybrid offspring mice with telomerase rebuilt the shortest telomeres just enough to restore telomere function, rather than lengthening all telomeres or dramatically lengthening the short ones, says Hemann. These mice had no chromosomal rearrangements or excess cell death, even though their average telomere length was similar to their telomerase-null siblings, says Hemann.
Other authors on the study are Margaret Strong and Ling-Yang Hao of Hopkins.

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