For some time, researchers have investigated the role that telomeres¿coverings on the tips of chromosomes¿play in moderating cell growth, mutation and death. In doing so, they have generally measured the average lengths of these chromosomal caps, which are shortened each time the cell divides. But in a study published in today¿s issue of the journal Cell, Carol Greider and colleagues at the Johns Hopkins University School of Medicine report that it is actually the single shortest telomere in a cell that controls its fate.
The researchers bred telomerase-null mice, which have very short telomeres and lack the telomerase enzyme needed to rebuild them, with mice having active telomerase and correspondingly long telomeres. The offspring all had telomeres of intermediate length, but one-quarter also inherited telomerase and with it, the ability to rebuild their telomeres.
Greider and team found that cell mutations in the mice occurred when telomeres on only one or two chromosomes were nearly gone. "Our evidence suggests that once a telomere becomes very short, the cell recognizes it as a DNA break," Greider notes. "Broken DNA commonly signals normal cells to arrest or die as a protection against chromosome rearrangement and cancer." Most importantly, the offspring without telomerase experienced cell death equivalent to that of their short-telomered parent, despite having a longer average telomere length.
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The scientists also determined that telomerase saved cells in the second-generation mice by lengthening only the shortest telomeres instead of acting on them all indiscriminately. The enzyme also seemed to save itself extra work: it lengthened the telomeres just enough to restore function and no more. The findings, Greider says, represent "a fundamental change in the way that most scientists think about telomere length."