Mechanisms Governing Disruption of Telomere Maintenance in Dyskeratosis Congenita

Dyskeratosis congenita (DC) is a bone marrow failure syndrome characterized by widespread defects in diverse tissues and a strong predisposition to cancer. DC is caused by germline mutations in genes controlling maintenance of telomeres, nucleoprotein caps that protect chromosome ends. DC is part of a larger collection of telomere disorders whose manifestations include pulmonary fibrosis, liver cirrhosis and defects in many other tissues. Mutations in components of the telomerase enzyme comprise a large share of cases, including in TERT, TERC, dyskerin, TCAB1, NOP10 and NHP2. These mutations compromise telomerase function leading to telomere shortening, which in turn impairs stem cell function. The telomerase holoenzyme operates according to a complex cycle of assembly, nuclear trafficking, recruitment to telomeres and catalytic action to elongate telomeres. In patients with telomere disease states, each of these steps can be impaired leading to a common set of disease phenotypes. We previously created patient-derived iPS cells from patients with mutations in TERT, dyskerin or TCAB1 and analyzed these cells to understand the biochemical defects in the telomerase pathway. Molecular defects in these patients operate according to diverse mechanisms including: reduced catalytic function, impaired telomerase assembly, mislocalization of the enzyme to nucleoli and defective recruitment to telomeres. The development of therapeutics to treat these disease states will require approaches targeted to the underlying molecular defects in each form of the disease.