Control of protein synthesis through mRNA pseudouridylation by dyskerin

Abstract

Posttranscriptional modifications of mRNA have emerged as regulators of gene expression. Although pseudouridylation is the most abundant, its biological role remains poorly understood. Here, we demonstrate that the pseudouridine synthase dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a guide RNA with full complementarity. In cells lacking dyskerin, mRNA pseudouridylation is reduced, while at the same time, de novo protein synthesis is enhanced, indicating that this modification interferes with translation. Accordingly, mRNAs with fewer pseudouridines due to knockdown of dyskerin are translated more efficiently. Moreover, mRNA pseudouridylation is severely reduced in patients with dyskeratosis congenita caused by inherited mutations in the gene encoding dyskerin (i.e., DKC1 ). Our findings demonstrate that pseudouridylation by dyskerin modulates mRNA translatability, with important implications for both normal development and disease.

The zebrafish (Danio rerio) snoRNAome

“…Accumulating evidence suggests that pseudouridylation of mRNAs is also abundant and can affect the efficiency of gene expression (Carlile et al 2014;Schwartz et al 2014;Li et al 2015;Martinez et al 2022;Nir et al 2022;Rodell et al 2023;Zhang et al 2023;Sun et al 2023;Hamar and Varga 2023). As different studies identified different roles for pseudouridines in mRNA (Dai et al 2022;Pederiva et al 2023), the exact role for this modification (which is most likely to be context-dependent) remains to be confirmed.…”

C-Ribosylating Enzymes in the (Bio)Synthesis of C-Nucleosides and C-Glycosylated Natural Products

“…PUSs are ubiquitous enzymes that modify RNA post-transcriptionally . They convert specific U positions into Ψ ( 2a ) in many types of RNA (tRNA, mRNA, rRNA, snRNA, snoRNA, and scaRNA). − Modification with Ψ affects RNA function (e.g., translation, splicing) and stability. − Disregulation of the PUS has been linked to various diseases, − including cancer. , PUS-like enzymes provide the intermediary Ψ for the biosynthesis of C -riboside antibiotics (Figure ), such as malayamycin ( 6 ) and pseudouridimycin ( 7 ). Malayamycin ( 6 ) has antifungal activity by inhibiting sporulation .…”

Transcriptomic analysis reveals prognostic molecular subtype and candidate risk model for pseudouridylation- related genes in hepatocellular carcinoma

“…It has been reported that Ψ can affect pre-mRNA processing by modifying pre-mRNA 10 , suggesting that it has great potentiality to regulate human gene expression. Certainly, there are growing evidences indicated that pseudouridylation plays an important role in regulating translation and gene expression [11][12][13][14] . For cancers, PUS7-dependent tRNA modi cation was found to control the growth of glioblastoma stem cells by controlling the translation of some key GSC regulators in glioblastoma 15 , and PUS1-mediated pseudouridylation enhances the translation of many oncogenes, which promoting the progression of HCC 16 .…”