Insights Into Cellular Regulation of Chromosome “Caps”

Researchers identified a key regulator of human telomere length with potential implications for diseases and disorders of telomere biology as well as broadly for human health. Telomeres are sequences of DNA found on the ends of chromosomes—the structures in which DNA is organized within a cell. When a cell divides, a bit of DNA sequence from the chromosome end is lost naturally. This shortening is counteracted by a protein that synthesizes new telomeric DNA, so telomeres act as a “cap” to protect the critical genetic information from degradation and keep chromosomes stable. Natural telomere shortening is a hallmark of aging and is associated with increased incidence of disease, including age-related diseases, and poorer outcomes. In addition, disruption of telomere maintenance (such as through inherited genetic alterations) can cause a number of conditions including bone marrow failure, cardiovascular disease, lung disease, liver cirrhosis, and cancer. Bone marrow failure syndromes, also known as telomere biology disorders, lead to impaired blood production. Therefore, understanding the regulation of human telomere length is vital to developing treatments for a variety of diseases and disorders and promoting human health.

Using an approach that allowed them to screen a large number of genes for effects on telomere length in human cells in the laboratory, scientists identified the molecule thymidine (one of the building blocks [bases] of DNA), and genes that affect levels of thymidine, as important regulators. When genes predicted to promote production of thymidine were turned off, the scientists observed short telomeres in the cells. Conversely, when genes predicted to decrease levels of thymidine, such as the thymidine-degrading gene SAMHD1, were turned off, they found longer telomeres. Interestingly, this regulation appeared to be specific and unique to thymidine; altering the levels of the other three DNA bases did not have the same effect. The researchers also demonstrated similar effects when supplementing the cells with thymidine or treating the cells with small molecules that decreased thymidine production. These results suggest a novel and key role for thymidine in regulating telomere length.

Given that some current therapies for cancer and other diseases alter production of molecules like thymidine, the scientists tested whether a similar approach might have potential to treat telomere biology disorders. They found that supplementation of thymidine in cells from people with different telomere biology disorders promoted telomere lengthening, suggesting the possibility of a new therapeutic strategy. This promising approach will need to be studied in animals, including humans, to determine whether the effects are similar to those observed in the laboratory and to develop further this exciting advance.