ARE tiny rings of DNA killing you slowly? Researchers have discovered that natural gene circles cause single-celled yeast-and perhaps people-to grow old and die. The circles hog the machinery for normal chro- mosome replication, halting cell division. Links between ageing in people and lowly yeast emerged following the cloning of a human gene dubbed WRN last year. Defects in this gene are the cause of Werner's syndrome, a disease which turns people grey and wrinkly at 20, and usually kills them before they reach 50. Three months ago, a team led by Leonard Guarente of the Massachusetts In- stitute of Technology reported that faults in the yeast version of the WRN gene, called SGSI, also made the yeast cells grow old quickly. The life span of the cells decreased by 60 per cent, suggesting that WRNISGS1 rz is a longevity factor for a wide range of species (This Week, 6 September, p 14). :z The puzzle that remained was why defects in either gene should summon mor- tality's shadowy hand. Guarente guessed the answer lay in the nucleolus, the cres- cent-shape structure in the cell where the protein produced by SGSI was concen- trated. In nearly every cell of higher organisms, the nucleolus is where riboso- mal DNA (RDNA) is copied to build pieces of the ribosomes-the protein factories of the cell. "The obvious thing to do was to look at that DNA," says Guarente. In yeast, as in humans, there are many copies of RDNA genes arranged end-to-end on linear chromosomes. Guarente and his colleague David Sinclair report in last week's issue of Cell (vol 91, p 1033) that in young yeast cells, that was all they found. But in older cells or young cells with the SGS1 defect, they found circular molecules that contained one or more RDNA genes. The researchers believe these circular molecules were looped out when adjacent rDNA genes exchanged DNA. Once free of the confines of a chromosome, the loops replicated rapidly until they made up about half the DNA in the nucleus.
The team then checked that the circles were the cause of ageing, and not just an- other symptom of old age. They used the tricks of genetic engineering to create a copy of one piece of RDNA that popped into a circle when its yeast host was fed the nutrient galactose. Normal yeast divided about 40 times on this diet. But identical cells with the engineered gene managed only 20 or so divisions before they expired. Guarente believes that the protein pro- duced by WRNISGSI normally extends life span by slowing the production of the circles. His team hopes to find molecules that stop the progress of the deadly loops in a similar way. "The work is very exciting," says George Martin of the University of Washington in Seattle, part of the team that cloned the WRN gene. "It provides a good target for researchers to focus on." Philip Cohen