BioWorld International Correspondent
LONDON - Understanding how the chromosomes preserve - or lose - their protective tips, called telomeres, is crucial for many aspects of research into cancer and aging. A new study has pinpointed a protein complex that plays an important role in maintaining telomeres.
Telomeres are the repetitive strips of DNA found at the ends of chromosomes. In many cells, each time they divide, the telomeres get shorter until eventually they disappear altogether, and the cell enters a pathway leading either to senescence or apoptosis.
The enzyme telomerase helps the cell to maintain its telomeres. Telomerase is not expressed in most adult human cells, but it is active in 90 percent of human cancer cells: Many studies have focused on ways of inhibiting the enzyme in cancer cells, to force them to undergo apoptosis.
An international team of researchers now has identified a protein complex that, in yeast, helps the telomeres to elongate. Since many of the same proteins in the complex have human analogues, it is likely that those, too, are involved in telomere regulation in human cells.
David Lydall, professor of the biology of aging at the Institute for Ageing and Health at the University of Newcastle in Newcastle upon Tyne, UK, told BioWorld International: "We have identified a new set of proteins that appear to partially open the ends of the chromosomes and make the ends available to telomerase, so maintaining telomere length. If you were able to make a pharmaceutical to inhibit this complex, you might be able to allow old cells that have divided many times to divide a few more times before they stopped dividing altogether - this could perhaps allow the immune system to work for longer in an elderly person, for example."
Lydall, together with collaborators in Toronto; Vienna, Austria; and elsewhere in the UK, published an account of the study in the March 23, 2006, issue of Cell in a paper titled "A Genome-Wide Screen Identifies the Evolutionarily Conserved KEOPS Complex as a Telomere Regulator." The first author is Michael Downey from the lab of Daniel Durocher at Mount Sinai Hospital in Toronto.
A primary function of the telomeres is to prevent the cell from recognizing the ends of the chromosomes as DNA damage. If the cell perceives telomeres as naked DNA ends, it will join the two chromatid ends to each other.
Lydall, Durocher and their colleagues were studying telomeres and telomerase in yeast, because telomerase is expressed in budding yeast cells. They already knew that a yeast protein called Cdc13 plays an essential role in capping the chromosome ends.
A mutant known as cdc13-1 grows well at 23 degrees Celsius, but at temperatures as high as 36 degrees Celsius, the telomeres become uncapped and the cells enter senescence.
Earlier work by the team had shown that, at intermediate temperatures, the telomeres were partially uncapped and that it was possible to improve the growth of the mutant cells by disabling aspects of the DNA damage response.
As reported in the Cell paper, the group took cdc13-1 mutants and crossed them with cells from a library of mutants in which each gene had been deleted in turn. The result was 4,800 double mutants, which grew at room temperature.
Lydall said: "We then asked, Do the double mutants grow better than a single cdc13-1 mutant?’ We knew that if we disabled DNA damage repair pathways, the cdc13-1 mutants can grow a little bit better - specifically, they can form colonies at 27 degrees Celsius. But cells that have their DNA damage repair pathways intact will not form a colony at this temperature - their telomeres are uncapped, and the cell enters cell-cycle arrest."
The study allowed them to identify a protein that exists in what’s called the KEOPS complex. That complex appears to be involved in opening the telomere enough for telomerase to function, Lydall said, while at the same time keeping it capped to hide it from the DNA damage response.