Mutation In DKC1 Gene Can Cause Rare Aging Disease And Cancer

This is the first example that shows that a defect in ribosome function may cause cancer, said Davide Ruggero, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and first author of the study. In the past, we thought of ribosome as an important but passive machine in the synthesis of proteins while our study suggests that it plays a more active role in maintaining proper cellular function.

Dyskeratosis Congenita is an extremely rare, fatal X-linked recessive disease that results in premature aging, severe anemia due to bone marrow failure, and dyskeratosis of the nails, skin hyperpigmentation, and cancer. It is caused by mutations in the DKC1 gene that encodes a protein named dyskerin, which is widely distributed in tissues. Dyskerin is thought to be involved in the regulation of ribosomal function and interacts with the RNA component of telomerase, which is essential in the regulation of telomere length. Patients with DC have in fact, unusually shortened telomeres, which was hypothesized to cause the various features of the disease including genomic instability and, in turn, cancer susceptibility.

In this study, (the) Dkc1 mutant mice were generated that were an accurate model of the human disease and duplicated the same phenotypes found in DC. However, since mouse telomeres are longer than those of humans, the disease was not predicted to occur until telomeres reached a critical reduction in length which would take several generations of the Dkc1 mutant strain. Surprisingly, all the major features of DC including premature aging, dyskeratosis of the skin, bone marrow failure, and susceptibility to tumor development showed up in the first and second generation mice. However, overt defects in telomere length were, as expected, only evident beginning with the fourth or fifth generations. This showed that the primary cause of DC was not telomerase impairment. Rather, the deregulated ribosome function found in Dkc1 mutant mice was the primary cause of the syndrome. Telomerase deficiency may nevertheless exacerbate the disease and needs further study.

Our results proved that mutations to the DKC1 gene cause DC with its premature aging, bone marrow failure and cancer, explained Pier Paolo Pandolfi, M.D., Ph.D. head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. In fact, fifty percent of the Dkc1 mice developed malignant tumors with the most common sites for these cancers being lung and breast, he added, noting that this suggests ribosome malfunction is important in the genesis of cancer and may have clinical implications for the identification of new molecular targets for cancer drugs.

The study published in Science is the work of Drs. Davide Ruggero, Pier Paolo Pandolfi, Carlos Cordon-Cardo, Silvia Grisendi, Francesca Mari, and Francesco Piazza of Memorial Sloan-Kettering; Dr. Eduardo Rego of Memorial Sloan-Kettering and University of Sao Paolo Brazil; and Dr. Pulivarthi H. Rao of Baylor College of Medicine.

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