Effects of rare, devastating disease linked to shrinking of cells’ telomeres

BOSTON – Scientists at Dana-Farber Cancer Institute and their colleagues have found that much of the widespread damage that the rare genetic disease ataxia telangiectasia, or AT, wreaks on the body results from the progressive shortening of telomeres, the structures that cap the ends of a cell’s chromosomes.

In genetically altered mice, the researchers found that the shortening of telomeres led to a “crisis” that disrupted chromosomes “like a hand grenade thrown into the cell,” as one scientist put it. The resulting cellular chaos was manifested throughout the rodents’ bodies by the loss of reparative stem cells that different organs normally have in reserve, producing symptoms of premature aging such as hair loss and slow wound healing, and early death.

The report by Kwok-Kin Wong, MD, PhD, and Ronald A. DePinho, MD, of Dana-Farber and their collaborators was posted by Nature today on its website as an advance online publication, and it will appear in a forthcoming print issue of the journal.

“There are significant implications for humans” in the discovery, said DePinho, whose laboratory has made a number of fundamental findings about telomeres and their role in aging, cancer and problems like liver cirrhosis. “It suggests that much of the problems in AT are related to eroding telomeres. It provides us with a point of attack.” For example, it might be possible someday to restore telomere function with drugs and potentially reduce some of the ravages of the disease, DePinho says.

The study advances the understanding of telomeres’ implication in fundamental health problems like cancer, organ failure, premature aging and shortened lifespan. The findings also reveal the complexity of this effect and highlight differences between the disease in mice and humans, explains DePinho, who is also on faculty at Brigham and Women’s Hospital and Harvard Medical School.

Telomeres are protein structures that protect the ends of linear chromosomes like the plastic or metal ends of shoelaces. They are made by the cell using an enzyme called telomerase. The telomeres enable the cell to reproduce the ends of the chromosomes during cell division (chromosomes contain the DNA blueprints of the cell). But over time, repeated cell division causes the telomeres to shrink, and when they are eroded to a certain point, the cell stops dividing and dies. In cancer cells, activity of the enzyme telomerase maintains the length of the telomeres and consequently the cells keep dividing long past their normal life span.

In humans, AT is a genetic disease that occurs in about 1 in 40,000 births. Beginning in the first few years, patients gradually lose their ability to walk and are unusually prone to frequent infections and various types of cancers.

AT is fundamentally caused by a mutation in a gene, Atm, which makes a protein that is involved in sensing and coordinating repair of DNA. Atm also helps maintain telomere length in normal cells. Thos new study shows that the gene mutation and the shrinking of telomeres are jointly responsible for the far-reaching damage that AT causes in the body.

Scientists in DePinho’s laboratory, which produce a number of types of genetically modified mice to mimic human cancers and other diseases, created mice that lacked both the Atm gene and the gene needed for the cell to make telomerase. But because mice have much longer telomeres than humans, AT-like symptoms related to telomere shortening would be delayed or might not show up at all. So the scientists interbred these compound mutant mice to generate successively shorter telomeres so that they could measure the effects of telomere length on the disease manifestations.

In the mice with shortened telomeres, cells became genetically unstable and died, resulting in the degenerative changes seen in premature aging, organ failure, and early death. The combination of the mutant Atm and shortened telomeres, however, resulted in a “near complete suppression” of lymphomas that are common in mice and AT patients.

With AT patients, the would-be cancer cells maintain the capacity to activate telomerase, enabling genetically unstable lymphoid cells to become cancers. In the genetically altered mice, the researchers knocked out telomerase, thereby suppressing the lymphomas. The researchers were then able to follow the mice longer and, ultimately, to uncover signs and symptoms of premature aging – a prominent feature of the AT condition in humans.

“This study reveals the complexity of the genetic interactions between Atm deficiency and telomere dysfunction” in living mice, the authors wrote.

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The paper’s coauthors are Richard Maser, PhD, Robert Bachoo, MD, PhD, Daniel Carrasco, MD, PhD, of Dana-Farber; Jayant Menon, University of California, Los Angeles; Yansong Gu, PhD, University of Washington; and Frederick Alt, PhD, Center for Blood Research.

The research was funded in part by the National Institutes of Health and the American Cancer Society.