Dyskeratosis congenita (DKC) is a collection of autosomal dominant diseases that result in abnormalities in the skin, nails, bone marrow and lungs. DKC arises from hereditary mutations in factors that replenish or cap telomeres, which are at the ends of the chromosomes. When the level of telomere-replenishing factors dips, telomeres erode and chromosomes rearrange. The affected cells either die or become unable to divide. Patients with DKC often die before the age of 30, usually from infection because of bone marrow dysfunction, or as a result of their increased predisposition to cancer.

The authors use a mouse model that resembles DKC in humans to detemine the potential for adaptive extension of telomeres. They use mTert mice, which express one functional allele and one disrupted allele of the telomere-replenishing factor, telomerase reverse transcriptase (Tert). The initial generations of mTert heterozygotes exhibit the same telomere erosion as seen in DKC patients. The authors show that, after several generations, telomeres in mTert mice are restored to nearly the same lengths as those found in normal animals. This restoration depends on the inheritance of Tert, which actively supports lengthening of the telomeres. The telomere length restoration that is observed prevents cell death, and the mice do not exhibit phenotypes that are normally associated with loss of telomere function in the intestine, testes and the bone marrow. This result is similar to findings in yeast but shows that telomerase can correct telomere length over time in a mammal.

The ability to maintain a functional telomere cap appears to be more important than the actual length of the telomere itself. In yeast cells, long telomeres are bound by factors that inhibit telomere extension by telomerase. Short telomeres are not bound by as many inhibitory factors and telomerase can gain access and extend the telomere. The authors speculate that such an equilibration process might protect normal human stem cells. Furthermore, activation of the process in DKC-affected cells might reduce symptoms of the disease that result from lost telomere function. The capacity to lengthen telomeres in normal tissues with low levels of telomerase activity might also protect against the inhibition of telomerase during cancer therapy, and improve its efficacy.

2009