Naturally occurring mutations in the ribonucleoprotein reverse transcriptase, telomerase, are associated with the bone marrow failure syndromes dyskeratosis congenita (DKC), aplastic anemia (AA), and idiopathic pulmonary fibrosis (IPF). However, the mechanism by which these mutations impact telomerase function remains unknown. Here we present the structure of the human telomerase c-terminal extension (CTE or thumb domain) determined by the method of single-wavelength anomalous diffraction (SAD) to 2.31 A resolution. We also used direct telomerase activity and nucleic acid binding assays to explain how naturally occurring mutations within this portion of telomerase contribute to human disease. The single mutations localize within three highly conserved regions of the telomerase thumb domain referred to as motifs E-I, (thumb loop and helix) E-II and E-III (the FVYL pocket, comprising the hydrophobic residues F1012, V1025, Y1089 and L1092). Biochemical data shows that the mutations associated with DKC, AA and IFP disrupt the binding between telomerases protein subunit reverse transcriptase (TERT) and its nucleic acid substrates leading to loss of telomerase activity and processivity. Collectively our data shows that although these mutations do not alter the overall stability or expression of TERT, these rare genetic disorders are associated with an impaired telomerase holoenzyme that is unable to correctly assemble with its nucleic acid substrates, leading to incomplete telomere extension and telomere attrition, which are hallmarks of these diseases.
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