Deanna MacNeil from the Autexier lab establishes how an imbalance favoring telomerase RNA degradation over correct maturation is causative for the premature aging telomere biology disorder dyskeratosis congenita.
The telomerase holoenzyme responsible for maintaining telomeres in vertebrates requires many components in vivo, including dyskerin. Dyskerin binds and regulates the accumulation of the human telomerase RNA, hTR, as well as other non-coding RNAs that share the conserved H/ACA box motif. The precise mechanism by which dyskerin controls hTR levels is unknown, but is evidenced by defective hTR accumulation caused by substitutions in dyskerin, that are observed in the X-linked telomere biology disorder dyskeratosis congenita (X-DC). To understand the role of dyskerin in hTR accumulation, we analyzed X-DC substitutions K39E and K43E in the poorly characterized dyskerin N-terminus, and A353V within the canonical RNA binding domain (the PUA). These variants exhibited impaired binding to hTR and polyadenylated hTR species, while interactions with other H/ACA RNAs appear largely unperturbed by the N-terminal substitutions. hTR accumulation and telomerase activity defects of dyskerin deficient cells were rescued by wildtype dyskerin but not the variants. hTR 3 extended or polyadenylated species did not accumulate, suggesting hTR precursor degradation occurs upstream of mature complex assembly in the absence of dyskerin binding. Our findings demonstrate that the dyskerin-hTR interaction mediated by PUA and N-terminal residues of dyskerin is crucial to prevent unchecked hTR degradation.