The “Fifth” RNA Nucleotide: A Role for Ribosomal RNA Pseudouridylation in Control of Gene Expression at the Translational Level

McMahon, Mary; Bellodi, Cristian; Ruggero, Davide

doi:10.1007/978-1-4614-3991-2_13

Cited by 2 publications

(5 citation statements)

References 189 publications

(246 reference statements)

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“…The contribution of the noncoding genome to human disease is a rapidly expanding and important avenue of research, particularly in light of findings that the expression and function of several classes of ncRNAs are frequently altered in diseases such as cancer and developmental and neurological disorders . There is now an emerging realization that snoRNAs, whose origins lie in archaea, do not simply exhibit housekeeping roles in the production of ribosomes, but instead have evolved to regulate accurate and efficient translation by modulating post‐transcriptional rRNA modifications . Thus, the function of H/ACA snoRNAs may be similar to primordial RNA‐based mechanisms of gene expression regulation present in an ‘RNA world’.…”

Section: Resultsmentioning

confidence: 99%

“…89 There is now an emerging realization that snoRNAs, whose origins lie in archaea, 84 do not simply exhibit housekeeping roles in the production of ribosomes, but instead have evolved to regulate accurate and efficient translation by modulating post-transcriptional rRNA modifications. 63 Thus, the function of H/ACA snoRNAs may be similar to primordial RNA-based mechanisms of gene expression regulation present in an 'RNA world'. Furthermore, it is likely that H/ACA snoRNA-mediated translational regulation may play a particularly important role in cellular physiology and cell fate decisions.…”

Section: Resultsmentioning

confidence: 99%

“…One clue as to the functional importance of pseudouridine modifications on rRNA is that pseudouridine residues tend to cluster within regions of rRNA critical for modulating ribosome activity, namely the decoding center and peptidyl transferase center (PTC). In fact, a role for rRNA pseudouridine modifications in affecting specific aspects of ribosome function is evident from findings in yeast, mouse, and human cells, demonstrating that rRNA pseudouridine modifications influence translational fidelity, stop codon recognition, and ribosome–ligand interactions . Therefore, alterations in rRNA pseudouridylation levels may have profound effects on the ribosome's ability to accurately and efficiently translate messenger RNA (mRNA).…”

Section: Role For H/aca Snorna‐guided Rrna Pseudouridine Modificationmentioning

confidence: 99%

“…In fact, a role for rRNA pseudouridine modifications in affecting specific aspects of ribosome function is evident from findings in yeast, mouse, and human cells, demonstrating that rRNA pseudouridine modifications influence translational fidelity, stop codon recognition, and ribosome-ligand interactions. [60][61][62][63] Therefore, alterations in rRNA pseudouridylation levels may have profound effects on the ribosome's ability to accurately and efficiently translate messenger RNA (mRNA). These observations add to and support a growing body of evidence that structural components of the ribosome modulate specific aspects of protein synthesis.…”

Section: Role For H/aca Snorna-guided Rrna Pseudouridine Modificationmentioning

confidence: 99%

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

2014

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Role For H/aca Snorna‐guided Rrna Pseudouridine Modificationmentioning

confidence: 99%

Section: Role For H/aca Snorna-guided Rrna Pseudouridine Modificationmentioning

confidence: 99%

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

2014

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“…Consequently, while considerable progress has been made in our understanding of how nucleotide modifications affect conformation and function of small RNAs, it is currently impossible to predict their global impact on larger, more complex RNAs, such as rRNA. The currently accepted hypothesis is that rRNA modifications enhance the general stability of ribosomes and fine-tune their structure to promote efficient and precise translation (Decatur and Fournier 2002;Chow et al 2007;McMahon et al 2013). However, to date only a handful of studies demonstrating the importance of rRNA modifications for correct ribosome function have been reported.…”

Section: Introductionmentioning

confidence: 99%

A cluster of methylations in the domain IV of 25S rRNA is required for ribosome stability

Gigova

Duggimpudi

Pollex

et al. 2014

RNA

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In all three domains of life ribosomal RNAs are extensively modified at functionally important sites of the ribosome. These modifications are believed to fine-tune the ribosome structure for optimal translation. However, the precise mechanistic effect of modifications on ribosome function remains largely unknown. Here we show that a cluster of methylated nucleotides in domain IV of 25S rRNA is critical for integrity of the large ribosomal subunit. We identified the elusive cytosine-5 methyltransferase for C2278 in yeast as Rcm1 and found that a combined loss of cytosine-5 methylation at C2278 and ribose methylation at G2288 caused dramatic ribosome instability, resulting in loss of 60S ribosomal subunits. Structural and biochemical analyses revealed that this instability was caused by changes in the structure of 25S rRNA and a consequent loss of multiple ribosomal proteins from the large ribosomal subunit. Our data demonstrate that individual RNA modifications can strongly affect structure of large ribonucleoprotein complexes.

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The “Fifth” RNA Nucleotide: A Role for Ribosomal RNA Pseudouridylation in Control of Gene Expression at the Translational Level

Cited by 2 publications

References 189 publications

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

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

A cluster of methylations in the domain IV of 25S rRNA is required for ribosome stability

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