The long-term goal of this work is to understand the pathogenesis of the rare bone marrow failure syndrome dyskeratosis ongenital (DC) and the reasons for its predisposition to malignancy. X-linked DC caused by mutations in DKC1 encoding the protein dyskerin is the most common form of the disease. All forms of DC are known to have mutations in components of telomerase or shelterin, the telomere associated complex. Dyskerin is a component of small nucleolar ribonucleoprotein particles (snoRNP), which function in modification and processing of ribosomal RNA (rRNA) and small nuclear RNAs (snRNA) as well as being important for the assembly and stability of the telomerase complex. While strong evidence suggests that compromised telomerase function is the major cause of DC defects in dyskerin functions in other pathways may contribute to the development of the disease. The generally accepted mechanism for DC pathology is that the various mutations cause rapid telomere shortening leading to critically short telomeres that trigger cell senescence or apoptosis causing stem cell depletion and bone marrow failure. During the last funding period we discovered a novel pathway in dyskerin mutant cells conferring a growth disadvantage to the mutant cells independent of telomere length. Mutant mice showed accelerated aging of bone marrow stem cells. Based on these results we hypothesize that: 1. Dyskerin has a previously undiscovered role, as part of the telomerase complex, in the cell's response to DNA damage. Dysfunctional dyskerin therefore leads to the accumulation of DNA damage in aging cells. 2. Dyskerin mutant cells are hypersensitive to oxidative DNA damage. 3. Dyskerin in addition to its role in telomere maintenance may affect the expression of disease through its role in rRNA processing. For the following funding period we propose to further characterize the pathway responsible for this growth disadvantage and test whether this pathway is specific for X-linked DC or whether it applies for all genetic forms of the disease. We will further test whether antioxidant treatment can correct the stem cell defect in Dkc1 mutant mice. Finally, we will investigate the role of dyskerin in ribosome biogenesis and the processing of rRNA using our model of liver cells depleted of dyskerin developed during the last funding period. Findings are likely to provide further insights into the different functions of dyskerin in mammalian cells, to increase our understanding of the pathogenesis of this disease and its susceptibility to cancer, and to identify novel targets for the development of new more specific therapies for patients with DC or related conditions associated with accelerated stem cell aging.

Public Health Relevance

X-linked dyskeratosis ongenital (DC) is a human inherited disease in which patients develop severe anemia and have an increased likelihood of developing cancer. The current dogma was that bone marrow failure in patients with DC is caused by excessively short telomeres, which are the ends of chromosomes. The purpose of our studies is to generate genetically engineered mice that model the disease because they carry the same mutations as patients with DC. Interestingly, the analysis of these mice showed a new unexpected pathway that leads to the impairment of bone marrow cells before the telomeres are short. In this renewal we propose to further characterize this pathway and test whether this pathway is common to all forms of DC or specific to the X-linked form of DC. Furthermore we propose to test whether drug induced inhibition or reversal of the pathway will restore the normal growth of bone marrow cells, and may be developed into a new form of treatment or disease prevention for patients with DC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Hematopoiesis Study Section (HP)
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Pelroy, Richard
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Children's Hospital of Philadelphia
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Gu, Bai-Wei; Apicella, Marisa; Mills, Jason et al. (2015) Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients. PLoS One 10:e0127414
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