Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 0C7, Canada.
Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, H3T 1E2, Canada.
RNA. 2021 Dec;27(12):1441-1458. doi: 10.1261/rna.078953.121. Epub 2021 Sep 23.
Dyskerin and its homologs are ancient and conserved enzymes that catalyze the most common post-transcriptional 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 highlights 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 , 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.
核蛋白 dyskerin 及其同源物是古老而保守的酶，能够催化细胞中最常见的转录后修饰——假尿嘧啶化。由此产生的假尿嘧啶为 RNA 分子提供了稳定性，并调节核糖体的生物发生和剪接事件。核蛋白 dyskerin 并非独立发挥作用——它是一种蛋白四聚体的核心组成部分，该四聚体与含有 H/ACA 基序的 RNA 结合。指导该核糖核蛋白 (RNP) 复合物发挥功能的 H/ACA RNA 种类繁多，这突显了核蛋白 dyskerin 参与的细胞过程的多样性。当与小核仁 (sno) RNA 结合时，它调节核糖体 (r) RNA 和核糖体的生物发生。通过与小 Cajal 体 (sca) RNA 相互作用，它将小核 (sn) RNA 靶向到特定位置以调节前体 mRNA 的剪接。作为端粒酶全酶的组成部分，核蛋白 dyskerin 与端粒酶 RNA 结合以调节端粒的维持。在疾病背景下，核蛋白 dyskerin 的功能障碍会导致多种有害表型。编码核蛋白 dyskerin 的 基因突变会导致 X 连锁先天性角化不良（X-DC），这是一种仍无法治愈的疾病，通常会导致骨髓衰竭。在这篇综述中，我们介绍了这种必需蛋白的经典和最新发现，讨论了核蛋白 dyskerin 和 H/ACA RNP 的进化、结构和功能方面。最新的研究强调了核蛋白 dyskerin 在基因表达调控、翻译效率和端粒维持中的作用，以及功能缺陷的核蛋白 dyskerin 对衰老、细胞增殖、造血潜能和癌症的影响。
