Telomeres, the repetitive sequences on the ends of chromosomes, maintain chromosome stability; when they are lost, chromosomes rearrange, cells arrest and eventually die. Scientists at Johns Hopkins University show that the cellular response to telomere shortening depends on the length of the shortest telomere within a cell, rather than the commonly used measure: average telomere length.

Telomere length is maintained by a balance between the loss of telomere repeats (for example, through cell division) and the addition of new repeats by the enzyme telomerase, which is however turned off in most normal differentiated cells. Observations that average telomere length correlates with abnormal cell proliferation and cell senescence suggest that average telomere length dictates the cellular response to telomere shortening. In other words, if the number of repeats within a cell falls below a given threshold a response is elicited. But an alternative model is that individual, shortened telomeres trigger the response. In a paper published in the 5 October issue of Cell, the Hopkins group led by Carol Greider distinguishes between the two possibilities.

Building on their earlier work showing that shortened telomeres give rise to end-to-end chromosome fusions, the scientists crossed telomerase-null mice, which have short telomeres, with mice heterozygous for telomerase activity, which have long telomeres. The resulting hybrid mice have average telomere lengths that fall between those of the parental strains; however, only half of the mice have a working telomerase that can rebuild their telomeres.

Analysis of cells from the hybrid offspring that lack telomerase indicates that chromosome rearrangements start to occur when telomeres from one or two chromosomes are all but gone. The left-hand figure shows a metaphase spread of a cell taken from a hybrid mouse strain, stained with DAPI to identify fused chromosomes. A fusion in chromosome 19 is identified by the circle. The right-hand figure shows a different metaphase spread using cells from the same mouse and stained by Q-FISH to identify telomeres (red). The arrow points to a chromosome 19 that lacks a telomere signal. Thus, the chromosome with the shortest telomere is also the one involved in the fusions. An independent telomerase-null mouse line had different chromosomes with short telomeres and different chromosome fusions.

In contrast, the hybrid offspring mice with telomerase were able to rebuild the shortest telomeres just enough to maintain telomere function. These mice had no chromosomal rearrangements or excess cell death, even though their average telomere length was similar to the telomerase-null siblings.

The results suggest that once an individual telomere becomes very short it is recognized by the cell machinery as a DNA break and recombination occurs. This, in turn, signals the cell to arrest or die.