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Rrna and Trna Bridges to Neuronal Homeostasis in Health and Disease

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Rrna and Trna Bridges to Neuronal Homeostasis in Health and Disease Review rRNA and tRNA Bridges to Neuronal Homeostasis in Health and Disease Francesca Tuorto 1 and Rosanna Parlato 2,3 1 - Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany 2 - Institute of Applied Physiology, University of Ulm, Albert Einstein Allee 11, 89081 Ulm, Germany 3 - Institute of Anatomy and Cell Biology, Medical Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany Correspondence to Francesca Tuorto and Rosanna Parlato: German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. University of Ulm, Institute of Applied Physiology, Albert Einstein Allee, 11, 89081 Ulm, Germany. [email protected], [email protected] https://doi.org/10.1016/j.jmb.2019.03.004 Edited by Ernst Stefan Seemann Abstract Dysregulation of protein translation is emerging as a unifying mechanism in the pathogenesis of many neuronal disorders. Ribosomal RNA (rRNA) and transfer RNA (tRNA) are structural molecules that have complementary and coordinated functions in protein synthesis. Defects in both rRNAs and tRNAs have been described in mammalian brain development, neurological syndromes, and neurodegeneration. In this review, we present the molecular mechanisms that link aberrant rRNA and tRNA transcription, processing and modifications to translation deficits, and neuropathogenesis. We also discuss the interdependence of rRNA and tRNA biosynthesis and how their metabolism brings together proteotoxic stress and impaired neuronal homeostasis. © 2019 Elsevier Ltd. All rights reserved. Introduction at specific positions [4]. There are two main types of tsRNAs: tRNA-derived fragments (tRFs; 14–30 Types of RNA in a eukaryotic cell classically nucleotides) and tiRNAs (tRNA-derived stress- included ribosomal RNA (rRNA), transfer RNA induced RNAs, or tRNA halves, 28–36 nucleotides), (tRNA), and messenger RNA (mRNA). Over the last both regulating the translation machinery and cellular decade, advances in RNA-sequencing (RNA-seq) and homeostasis by multiple mechanisms, including transcriptome-wide analysis enabled the identification mRNA stability, inhibition of translation initiation and of an increasing variety of non-coding RNA, such as elongation, and ribosome biogenesis [5–8]. long non-coding RNA, microRNA, small nuclear RNA Recent reviews have outlined the up-to-date (snRNA), small nucleolar RNA (snoRNA), piwiRNA, functions of various RNA types in aging and age- and circular RNA (circRNA) increasing the complexity related diseases [1,4,9]. Here, we emphasize the of RNA-mediated regulation of physiological cellular emerging roles of dysfunctional rRNA and tRNA in processes and disease mechanisms [1]. Although neurological disorders in particular, but not exclu- rRNA and tRNA are usually excluded from these sively, those linked with cognitive decline and transcriptomic studies, recent findings promoted the neurodegeneration. After a brief summary of the need to revisit the function of these RNAs and their molecular and structural basis of rRNA and tRNA integration into mechanisms regulating protein syn- synthesis, we describe recent evidence of rRNA- thesis and beyond. In addition, a novel class of small and tRNA-mediated disease mechanisms. Finally, RNAs was revealed using the RNA-seq data [2,3]. we discuss how this knowledge can help the For instance, the fragmentation of tRNAs gives rise identification of new therapeutic approaches and to tRNA-derived small RNAs (tsRNAs) by the cleavage the development of disease markers. 0022-2836/© 2019 Elsevier Ltd. All rights reserved. Journal of Molecular Biology (2019) 431, 1763–1779 1764 Review: rRNA and tRNA Bridges to Neuronal Homeostasis Snapshots of rRNA Synthesis and sites within the ribosomes: they increase the stability of the ribosome, the precision of protein synthesis, Ribosome Biogenesis and ribosomal specialization [14]. Importantly, not all rRNA synthesis takes place in the nucleolus, a ribosomes are structurally and functionally identical nuclear compartment not surrounded by membrane [13], and specialized ribosomes turn up to be a novel in which ribosomal subunits are also assembled strategy to regulate gene expression [15].The (Fig. 1). Each rDNA repeat unit consists of a different affinity of ribosome components for specific conserved rRNA coding sequence transcribed by mRNAs is an emerging mechanism by which trans- the RNA polymerase I (RNA Pol I) and non- lation controls gene expression [16]. It has been conserved intergenic spacers. The mature 18S, reported that subsets of mRNAs, involved in the 5.8S, and 28S rRNAs derive from an rRNA precursor response to oxidative stress, depend on the loss of transcript (47S pre-rRNA) separated by externally specific rRNA modifications [17]. For example, the and internally transcribed spacers. The mature 80S reduced expression of the RNA methyltransferase ribosome is composed of two subunits: the small NSUN5, which catalyzes the post-transcriptional 40S ribosomal subunit that contains the 18S rRNA modification 5- methylcytidine (m5C) in the 28S and 33 ribosomal proteins (RPs) and the large 60S rRNA, results in both reduced rRNA methylation and ribosomal subunit that comprises the 28S, 5.8S, and altered translational fidelity, leading to increased 5S rRNAs and 47 RPs [10]. stress resistance by the translation of proteins Notably, the nucleolus consists of three regions important for the stress response, for example, corresponding to three different steps in the synthe- involved in DNA damage repair [17]. sis of rRNA and characterized by the expression of Interestingly, these rRNA modifications are regu- typical markers with a specific role in rRNA lated by nutrient availability and oxidative and heat synthesis. In particular, these regions are as follows: shock stress, tightening ribosome biogenesis and the fibrillar center (FC), where rDNA transcription function to environmental conditions, similarly to the takes place; the dense fibrillar component (DFC), reprogramming of tRNA modifications observed where pre-rRNA is processed; and the granular upon stress, that will be discussed later [18]. component (GC), also containing processing factors Moreover, the inhibition of rDNA transcription and ribosomal proteins. At the electron microscopic resulting in the loss of nucleolar integrity and release level, FCs are fibrillar regions enriched with RNA Pol of nucleolar proteins in the nucleoplasm defines a I–specific transcription factors including upstream condition known as “nucleolar stress” [19,20]. Lately, binding transcription factor 1 (UBTF1). DFCs are the functional implications of this condition have highly electron-dense fibrillar regions that surround been expanded by new evidence of the highly FCs. DFCs are labeled with antibodies specifically dynamic nature of nucleolar assembly and associated recognizing pre-rRNA processing factors including changes in protein composition [21]. An imbalance fibrillarin. GCs, the granular regions outside of FCs in ribosome biogenesis, for example, by the accumu- and DFCs, are enriched with assembly factors and lation of specific ribosomal proteins, may lead to an ribosomal proteins. During processing, the pre-40S increased stability of the transcription factors p53, a and the pre-60S ribosomal subunits are assembled major player in the response to different types of and exported to the cytoplasm where the mature cellular stresses [22]. Interestingly, not only nucleolar ribosomes are finally produced [11]. proteins are important for rRNA synthesis, they may Ribosomal biogenesis is a process that requires the also regulate cell proliferation, differentiation, and tight coordination of the transcriptional activity of all cell death [23]. The association between the nucleolus three RNA polymerases [12] that is in turn regulated and malignant cell transformation anticipated the by environmental changes. Post-translational modifi- hypothesis that this organelle might play an active cations of protein components of the transcriptional role in disease pathogenesis rather than being an end- machinery and histones as well as epigenetic effect of neoplastic transformation [19,24–27].Inthe modifications at the rDNA loci affect initiation of last decade, a similar hypothesis peeked out in the transcription [10]. Moreover, the structure and function context of neurodegenerative disorders [23,28–31]. of rRNAs are strongly influenced by a wide variety of Several mechanisms can be envisaged by which post-transcriptional modifications. These modifica- defective rRNA synthesis may have a deleterious tions regulate rRNA folding and within the ribosome impact on neuronal well-being, although surveillance are located in regions interacting with tRNA and mechanisms have been developed to detect and mRNA [9].2′-O-ribose-methylation (2′Ome) and eliminate misprocessed rRNA. Intriguingly, a silencing pseudouridylation (Ψ) are the most frequent rRNA mechanism that can inhibit pre-rRNA expression, if modifications in eukaryotes. Interestingly, these rRNA is not correctly processed, has been recently modifications are context-specific and depend on proposed [32]. extracellular changes, developmental and disease As summarized in Fig. 1, rRNA synthesis could be state [13]. rRNA post-transcriptional modifications dysregulated at different steps: changes in the number have various functions being located at functional of rDNA genes, defective rDNA transcription, and Review: rRNA and tRNA Bridges to
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