A little telomerase isn't enough

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Chromosome ends, or telomeres, are repetitive stretches of DNA that protect chromosomes in much the same way as plastic tips on shoelaces prevent the fabric from fraying. Each time a cell divides, its chromosome ends get a little shorter, and eventually the cell can no longer divide because its critical genetic information is exposed. In stem cells, however, a protein called telomerase normally maintains the telomeres' length, allowing the cells to divide indefinitely.

Now, the Hopkins researchers report that mice engineered to have just half the normal amount of telomerase can't maintain their stem cells' chromosome ends, showing that a little telomerase isn't enough. In these "half-telomerase" mice, their telomeres shortened over time, bringing an early demise to stem cells that replenish the blood supply, immune system and intestine, the researchers report. Moreover, offspring of these mice bred to have normal levels of telomerase still exhibited early loss of stem cells, the researchers report in the Dec. 16 issue of Cell.

"These offspring have what we have called 'occult' genetic disease - their genetic make-up is perfectly normal, but they still have the physical problems of their parents," says Carol Greider, Ph.D., director and professor of molecular biology and genetics in the Johns Hopkins Institute of Basic Biomedical Sciences. "This phenomenon could complicate the hunt for disease genes."

Scientists generally figure that inherited disease accompanies an inherited mutation in one or more genes. In the case of the genetically normal offspring of two half-telomerase parents, however, the disease is still present. The problem in these animals turns out to be the animal's inherited telomere length, not the status of the telomerase gene, says Greider.

"If you were to search for the genetic mutation behind this mouse's disease, you wouldn't find it - there isn't one," says Greider. "These mice develop disease only because their telomeres are short, and having telomerase doesn't lengthen them right away."

The condition of the mice is virtually identical to the human disease dyskeratosis congenita, which has already been linked to mutations in telomerase that hinder the protein's telomere-maintaining activity. In both mice and people with the condition, stem cells in bone marrow that replenish the blood cells and those in the digestive system that maintain the intestines can't divide as many times as they should and die early.

Because sperm and egg arise from stem cells, too, their telomeres gradually shorten, and each successive generation starts out with chromosomes whose telomeres are even shorter than their parents, the researchers report. The failure of telomerase to lengthen these telomeres explains why successive generations develop the physical symptoms of the disease at younger ages than their parents or grandparents, say the researchers.

In the Proceedings of the National Academy of Sciences in October 2005, Greider and her team reported their study of one family with dyskeratosis congenita. Mary Armanios, M.D., now an assistant professor of oncology in the Johns Hopkins Kimmel Cancer Center, discovered that the family carried a genetic defect that caused the telomerase protein to be half as effective as normal and that shortening telomeres were to blame for earlier onset.

In this family, the affected grandmother developed gray hair in her 20s and lung problems in her early 60s and died at age 65. Her affected children developed signs of the disease about 10 years earlier than she had, and analysis of their cells revealed that 60 percent to 75 percent of their chromosomes had dangerously short telomeres. In an affected grandson, signs of the disease appeared 40 years earlier than in his grandmother and 20 years earlier than in his father. Roughly 90 percent of the chromosomes in his cells had dangerously short telomeres.

"We know it only takes one critically short telomere to make a cell die, so it's clear that the more really short telomeres a person has the faster problems will develop," says Greider, whose lab reported the role of the critically short telomere in 2001.

The usual treatment for people with dyskeratosis congenita is a bone marrow transplant from an unaffected family member. But the team's new findings in mice suggest that the family member chosen for the transplant - if there's more than one option - should not only have normal telomerase levels but also have long telomeres compared to other family members.

"Normal levels of telomerase didn't lengthen short telomeres in our mice, so the longer the telomeres are to start with, the longer transplanted stem cells will be able to divide and the more likely the transplant is to succeed," explains Greider.

To engineer the half-telomerase mice, Ling-Yang Hao, then a graduate student, knocked out one copy of the telomerase gene in non-laboratory mice, whose telomere length is similar to humans'. (Typical laboratory mice have very long telomeres.)

He then bred these half-telomerase mice to one another and the team studied offspring that also carried just one telomerase copy. (Because one copy of each gene is inherited from each parent, only 50 percent of the offspring would be expected to end up with only one telomerase copy; 25 percent would have no telomerase gene, and 25 percent would have two copies of the telomerase gene.)

By the fifth generation, mice had severely shortened telomeres and exhibited failure of organs that have high turnover of their cells - the bone marrow and intestine among them.

"We thought there might be some relationship between telomerase, telomere length and the survival of stem cells, but it was really exciting to see it," says Greider.

When the researchers looked at fifth-generation mice that had by chance inherited their parents' good telomerase copies, giving the animals a full complement of telomerase, they were surprised to find that those mice had the same symptoms and problems as their half-telomerase littermates.

The researchers are now mating these short-telomere mice with mice with regular-length telomeres to see whether telomere length goes back up. They're also studying the affected stem cells to find out exactly how critically short telomeres are affecting their survival.

Johns Hopkins Medical Institutions