"Telomeres," Titia de Lange told BioWorld Today, "have two main problems right off the bat."

For one thing, telomeres - the ends of chromosomes - cannot be fully replicated when DNA is copied during cell division. Nature has made a virtue out of this so-called "end replication problem" and uses telomere length as an age gauge; short telomeres signal an old cell, and once telomere length falls below a critical point, further cell division becomes impossible and the cell dies.

But regardless of how long a telomere is, it always is a free-hanging piece of DNA. So another problem for cells is how to tell the difference between a DNA break, which will cause cellular chaos if it is not repaired posthaste, and the end of a chromosome, which will cause cellular chaos if it is "repaired."

Cells protect themselves against unwanted telomere repair, which will fuse their chromosomes into a single nonfunctional mass if given the chance, by binding a protein complex known as shelterin. The protein POT1 (Protector of Telomeres) is one part of the shelterin complex. And two papers in the July 14, 2006, issue of Cell reported new findings on POT1 - foremost among them, the fact that mice have two versions of the gene.

De Lange, who is a professor at Rockefeller University and senior author of one of the Cell papers, told BioWorld Today that such divergence between mouse and human genome "rarely happen. And they never happen in genes that are responsible for chromosome regulation."

"If you think about it," she added, "it suggests that the mice are evolved a little bit further, because the general trend in evolution is toward greater complexity." So in the matter of telomeres, at least, "humans, primates, cows and dogs lag behind rodents."

Aside from the basic scientific significance of the findings, they have practical implications for modeling human telomere biology in rodents. Whether for basic science or pharmaceutical research, animal modeling "assumes that the underlying basic biology is the same," de Lange pointed out. "But that assumption is challenged by our findings."

The shelterin complex also is of clinical interest because it interacts with telomerase, an enzyme that lengthens telomeres during development and in cancer cells. In the latter case, telomerase conveys an unfortunate immortality on cancer cells by keeping telomeres too long to trigger cell death. Telomerase is being targeted both as an anticancer strategy and in anti-aging and anti-HIV efforts, where researchers are attempting to activate telomerase to lengthen cellular lifespan.

"We knew from work we had done in human cells that POT1 is an important regulator of telomerase," de Lange said. "In human cells, if telomeres become too long, POT1 will switch off telomerase at that particular telomere."

The two mouse POT1 genes, though, turned out to work via a mechanism that is independent of telomerase.

From their previous work, the scientists suspected that shelterin's main function might be to load POT1 onto telomeres. Instead, de Lange and her colleagues showed that in mice POT1a is important for protecting against the DNA damage response; POT1b regulates the structure of the single-stranded overhang at the telomere tip, which is normally tucked back into the double-stranded DNA via shelterin to hide it from the cell's DNA processing machinery.

"POT1b knockouts have a single-stranded overhang that is too long," de Lange said. However, that is not due to any effects on telomerase: Double knockouts with neither POT1b nor telomerase still have the longer overhang.

The second paper, co-authored by scientists from the M.D. Anderson Cancer Center and Rice University in Houston; Hiroshoma University in Japan; and the Fort Collins Campus of Colorado State University, focused on the effects of knocking out 1a. The authors showed that POT1a deletion led to a damage response, as well as inappropriate homologous recombination.

De Lange's results provide further evidence for the existence of an enzyme that snips away at the telomeres, making the single-strand overhangs longer. Such an enzyme has not been identified, at least not in mammals, but de Lange noted that it would be "of obvious clinical interest," providing a potential new target for tweaking cell death.

Another line of evidence also suggests the existence of such a nuclease: "Human telomeres shorten much faster than you would expect from the end-replication problem," de Lange said. While the end-replication problem keeps chromosomes from replicating their last three base pairs during each round of cell division, telomeres actually lose anywhere from 50 to 150 base pairs per cell division.