Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance

Abstract

Dyskerin and its homologues are ancient and conserved enzymes that catalyse the most common posttranscriptional modification found in cells, pseudouridylation. The resulting pseudouridines provide stability to RNA molecules and regulate ribosome biogenesis and splicing events. Dyskerin does not act independently – it is the core component of a protein heterotetramer, which associates with RNAs that contain the H/ACA motif. The variety of H/ACA RNAs that guide the function of this ribonucleoprotein (RNP) complex highlight the diversity of cellular processes in which dyskerin participates. When associated with small nucleolar (sno) RNAs, it regulates ribosomal (r) RNAs and ribosome biogenesis. By interacting with small Cajal Body (sca) RNAs, it targets small nuclear (sn) RNAs to regulate pre-mRNA splicing. As a component of the telomerase holoenzyme, dyskerin binds to the telomerase RNA to modulate telomere maintenance. In a disease context, dyskerin malfunction can result in multiple detrimental phenotypes. Mutations in DKC1, the gene that encodes dyskerin, cause the premature aging syndrome X-linked dyskeratosis congenita (X-DC), a still incurable disorder that typically leads to bone marrow failure. In this review, we present the classical and most recent findings on this essential protein, discussing the evolutionary, structural and functional aspects of dyskerin and the H/ACA RNP. The latest research underscores the role that dyskerin plays in the regulation of gene expression, translation efficiency and telomere maintenance, along with the impacts that defective dyskerin has on aging, cell proliferation, haematopoietic potential and cancer.

A Novel Variant and a Missense Variant Identified in the DKC1 Gene in Three Chinese Familieswith Dyskeratosis Congenita

“…To our knowledge, DKC1 gene contains 15 exons that are translated into a ~58kDa L-shaped protein, dyskerin, which primarily presents with five domains: pseudouridine synthase domain (TRUB), pseudouridine synthase and archaeosine transglycosylase domain (PUA), dyskerin-like domain (DKCLD), nuclear and nucleolar localization signals (NLS/NoLS), amino-terminal extension (NTE), and carboxy-terminal extension (CTE). 22 , 23 As previously noted, mutations found in DKC1 mainly cause amino acid substitutions. Mutation sites are primarily distributed in exons 2–6 and 9–12, and c.1058C>T (p. A353V) in exon 11 is described as the most frequent site which is known to occur de novo in many cases.…”

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita

“…Pseudouridylation is one of the hundred post-transcriptional modifications of RNAs (transfer, messenger, ribosomal and spliceosomal). As a result, defective dyskerin causes premature aging and acffects cell proliferation and haematopoietic potential and cancer [ 63 ]. In addition, other genes responsible for DC direct important functions other than those conected with telomere function.…”

“…During follow-up, when the mucocutaneous triad is manifest, bone marrow failure is usually present. Sometimes, however, signs of the disease are vague and bone marrow failure or other abnormalities in another systems may present also before or in absence of the classical mucocutaneous traid [ 47 , 48 , 63 ]. Aplastic anemia, usually macrocytic with increased level of fetal hemoglobin, develops at an average age of onset of 11 years.…”

“…Aplastic anemia, usually macrocytic with increased level of fetal hemoglobin, develops at an average age of onset of 11 years. It is associated with thrombocytopenia and then evolves to severe bone marrow failure [ 47 , 48 , 63 ]. Bone marrow failure can progress with the appearance of myelodysplasia in one or more clones [ 4 ].…”

Dysregulation of Small Nucleolar RNAs in B-Cell Malignancies

“…Genes associated with snoRNA functions and biogenesis were found mutated in hematopoietic disease. For instance, DKC1 is mutated in inherited syndromes including X-linked dyskeratosis congenita (X-DC) and Hoyeraal–Hreidarsson syndrome, a clinically severe variant of dyskeratosis congenita (DC) and characterized by severe bone marrow failure [ 71 , 72 ]. Strikingly, only the expression of SNORNA15 and SNORNA67 was downregulated in DKC1-mutant CD34+ cells compared with normal CD34+ cells [ 70 ].…”