Small RNAs with big implications: new insights into H/ACA snoRNA function and their role in human disease

Abstract

A myriad of structurally and functionally diverse non-coding RNAs (ncRNAs) have recently been implicated in numerous human diseases including cancer. Small nucleolar RNAs (snoRNAs), the most abundant group of intron-encoded ncRNAs, are classified into two families (box C/D snoRNAs and box H/ACA snoRNAs) and are required for post-transcriptional modifications of ribosomal RNA (rRNA). There is now a growing appreciation that nucleotide modifications on rRNA may impart regulatory potential to the ribosome, however the functional consequence of site-specific snoRNA-guided modifications remains poorly defined. Discovered almost 20 years ago, H/ACA snoRNAs are required for the conversion of specific uridine residues to pseudouridine on rRNA. Interestingly, recent reports indicate that the levels of subsets of H/ACA snoRNAs required for pseudouridine modifications at specific sites on rRNA are altered in several diseases, particularly cancer. In this review, we describe recent advances in understanding the downstream consequences of H/ACA snoRNA-guided modifications on ribosome function, discuss the possible mechanism by which H/ACA snoRNAs may be regulated, and explore prospective expanding functions of H/ACA snoRNAs. Furthermore, we will discuss the potential biological implication of alterations in H/ACA snoRNA expression in several human diseases.

TRUB1 is the predominant pseudouridine synthase acting on mammalian mRNA via a predictable and conserved code

“…Ψ formation is catalyzed by diverse pseudouridine synthases (PUSs), which break the carbon-nitrogen bond of uridine and create a carbon-carbon bond by attaching the C5 position of the cleaved uridine to the ribose (Charette and Gray 2000). PUSs can either act in a site-specific manner, by directly recognizing their substrates, or can be guided to their targets via H/ACA box snoRNAs (Charette and Gray 2000;Spenkuch et al 2014;McMahon et al 2015).…”

Genome-wide analysis of small nucleolar RNAs ofLeishmania majorreveals a rich repertoire of RNAs involved in modification and processing of rRNA

“…46 We have recently begun to analyze the C at the wholetranscriptome genome level using a methodology similar to that used in recent studies that performed whole transcriptome mapping of this modification. 47 It will be of great interest to compare the pattern during the 2 life stages of the parasite and examine if these changes are correlated with growth at different temperatures, and/or are essential for preferential translation of distinct mRNAs which are developmentally regulated.…”

“…It was suggested that the translation of distinct mRNA species requires different types of modification and that a particular pattern is favored to translate mRNAs that are essential for the survival and metastasis of cancer cells. 46 Thus, novel snoRNAs with different function may arise in all organisms from Leishmania to man by just changing the pocket. Indeed, in Euglena as well, recent studies suggest that frequent gene duplication is a common mechanism driving snoRNA emergence leading to both a large number of snoRNAs and clustered patterning of rRNA modification.…”

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

“…The pseudouridylation of rRNAs, targeted by the H/ACA RNP complex, occurs in regions critical for ribosome activity such as the decoding center or peptidyl transferase domain. Pseudouridylation affects translation fidelity, stop codon usage and is required for IRES-mediated translation [76,78,79] . Alterations in the H/ACA snoRNP complex is most prominent in leukemias but is also altered in some solid tumors, including: prostate, head and neck, and non-small cell lung cancer [79] .…”