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Ribosomal Protein L10: from Function to Dysfunction

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Ribosomal Protein L10: from Function to Dysfunction cells Review Ribosomal Protein L10: From Function to Dysfunction Daniela Pollutri 1,2 and Marianna Penzo 1,2,* 1 Department of Experimental, Diagnostic and Specialty Medicine Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; [email protected] 2 Center for Applied Biomedical Research (CRBA), Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138 Bologna, Italy * Correspondence: [email protected]; Tel.: +39-051-214-3521 Received: 15 October 2020; Accepted: 16 November 2020; Published: 19 November 2020 Abstract: Eukaryotic cytoplasmic ribosomes are highly structured macromolecular complexes made up of four different ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs), which play a central role in the decoding of genetic code for the synthesis of new proteins. Over the past 25 years, studies on yeast and human models have made it possible to identify RPL10 (ribosomal protein L10 gene), which is a constituent of the large subunit of the ribosome, as an important player in the final stages of ribosome biogenesis and in ribosome function. Here, we reviewed the literature to give an overview of the role of RPL10 in physiologic and pathologic processes, including inherited disease and cancer. Keywords: RPL10; ribosome; cancer; ribosomopathy; rare disease; translation; protein synthesis 1. Introduction Eukaryotic cytoplasmic ribosomes are highly structured macromolecular complexes made up of four different ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs), which play a central role in the decoding of genetic code for the synthesis of new proteins. These two distinct yet complementary functions are separated into the two ribosomal subunits: the 40S (or small) and the 60S (or large) subunits, respectively. Even though the catalytic activity of ribosomes is held by rRNAs, many of the RPs are known to be essential for different steps and aspects of translation [1]. The process of ribosome production, ribosome biogenesis, is a highly coordinated process that takes place in the nucleolus, nucleoplasm, and cytoplasm. It involves (I) the transcription of rRNAs, which are extensively modified by a number of enzymatic complexes and enzymes, (II) the synthesis of RPs, and (III) the step-by-step assembly of rRNAs and RPs to form the mature large and small subunits (reviewed in [1]). Ribosome biogenesis is a highly energy-consuming process. Therefore, it is of great importance for the cell to synthesize all the components in a stoichiometric proportion; this goal is achieved primarily by means of a coordinated expression of the ribosomal proteins [2,3], which then participate in the regulation of rRNA transcription and modification [2,4]. Furthermore, to produce a sufficient number of functionally competent ribosomes, the cell has developed a number of quality checkpoints, which have been only partially identified to date [5]. Nevertheless, the emergence of variants of ribosomal constituents related to acquired or somatic mutations has been documented in several pathological settings [6–8]. In parallel, the old vision of “the ribosome” as a univocally determined, passive protein factory, has been replaced by the evidence-based awareness of ribosome diversity as a source of an additional level of gene expression control [6,7]. In this sense, the ribosome compositional diversification may be linked to physiological processes, such as cellular growth and differentiation, as well as to pathological conditions. Among the ribosome constituents that frequently undergo mutations in disease, there is RPL10 (uL16 in the new nomenclature [9]), also known as QM or DXS648 [10–12]. Although RPL10 mutations Cells 2020, 9, 2503; doi:10.3390/cells9112503 www.mdpi.com/journal/cells Cells 2020, 9, 2503 2 of 15 haveCells been 2020 reported, 9, x FOR PEER in numerous REVIEW inherited and acquired diseases, their impact on RPL10 ribosomal2 of 16 and extra-ribosomal functions, and, consequently, their role in the pathogenetic processes, has not mutations have been reported in numerous inherited and acquired diseases, their impact on RPL10 been completely determined. Here, we reviewed the literature concerning the known functions and ribosomal and extra-ribosomal functions, and, consequently, their role in the pathogenetic processes, alterationshas not of been RPL10, completely focusing determined. on the studies Here, conducted we reviewed in the the past literature decades concerning on eukaryotic the models.known functions and alterations of RPL10, focusing on the studies conducted in the past decades on 2. RPL10 Gene and Protein eukaryotic models. RPL10 is encoded by the RPL10 gene located on the X chromosome. RPL10 is listed among the L10e2. RPL10 family Gene members, and Protein which are the structural and functional orthologs of the L16 family in EubacteriaRPL10 [13 ].is encoded In a study by the on sequenceRPL10 gene changes located on in the XRPL10 chromosome.gene over RPL10 the is course listed among of evolution, the KlauckL10e and family colleagues members, found which that are the the translation structural product and functional of the gene orthologs has a highlyof the conservedL16 family aminoin acidEubacteria sequence [13]. from In yeast a study to human on sequence (about changes 67% protein in the identity,RPL10 gene Figure over1 )the and course archaea of evolution, (about 43% identity)Klauck [13 and]. This colleagues is true found in spite that of the remarkable translation genetic product di ffoferences, the gene such has a as highly variable conserved patterns amino in both exonsacid and sequence introns from length, yeast and to human in GC content,(about 67% probably protein leadingidentity, toFigure different 1) and splicing archaea and (about epigenetic 43% eventsidentity) [14]. For[13]. example, This is true mouse in spite RPL10 of remarkable differs from genetic its human differences, homolog such inas onlyvariable one patterns residue in (Figure both 1). exons and introns length, and in GC content, probably leading to different splicing and epigenetic Such an evolutionary conservation in the aminoacid sequence indicates the essential nature of RPL10 events [14]. For example, mouse RPL10 differs from its human homolog in only one residue (Figure in the biology of the organisms during the evolution. Although an increasing number of RPL10 1). Such an evolutionary conservation in the aminoacid sequence indicates the essential nature of extra-ribosomal functions are emerging, the strategic position close to catalytic center and regulatory RPL10 in the biology of the organisms during the evolution. Although an increasing number of sitesRPL10 within extra-ribosomal the ribosome functions evidences are a emerging, fundamental the strategic role of thisposition protein close in to ribosome catalytic integritycenter and and functionregulatory [13]. Indeed,sites within the essential the ribosome role of evidences this protein a isfundamental supported byrole the of identification this protein ofin anribosome autosomal intron-lessintegrityRPL10 and functionhomolog [13]. named Indeed,RPL10L the essential(ribosomal role of protein this protein L10-like is supported gene), mapping by the identification on chromosome 14 andof an showing autosomal about intron-less 96% identity RPL10 in homolog the aminoacid named sequence RPL10L (ribosomal (Figure1) andprotein a 90% L10-like identity gene), in the codingmapping sequence on chromosome compared to14 RPL10and showing. The identityabout 96% level identity was in determined the aminoacid by comparingsequence (Figure the cDNA 1) sequencesand a 90% of the identity two genes. in the coding Northern sequence blot analysis compared and to PCR RPL10 assays. The conductedidentity level by was Uechi determined and colleagues by in 16comparing human tissues the cDNA and eight sequences tumor-derived of the two cell lines,genes. showed Northern a testis-specific blot analysis expression and PCR ofassays RPL10L. Sinceconducted this gene by has Uechi no intronsand colleagues in its coding in 16 human region, tiss theyues concludedand eight tumor-derived that it was most cell lines, likely showed produced by retro-transpositiona testis-specific expression of the original of RPL10L. X-linked Since genethis gene in the has course no introns of the evolutionin its coding to compensateregion, they for concluded that it was most likely produced by retro-transposition of the original X-linked gene in the reduced dosage during spermatogenesis and to escape the meiotic sex chromosome inactivation the course of the evolution to compensate for the reduced dosage during spermatogenesis and to (MSCI) [15]. Indeed, RT-PCR assays of Rpl10L in male mouse germ cells at different developmental escape the meiotic sex chromosome inactivation (MSCI) [15]. Indeed, RT-PCR assays of Rpl10L in stages showed an increase in Rpl10L expression during meiosis specifically when Rpl10 is silenced male mouse germ cells at different developmental stages showed an increase in Rpl10L expression by MSCI.during Further meiosis experimentsspecifically when conducted Rpl10 is bysilenced Jiang by and MSCI. colleagues Further usingexperiments mouse conducted and human by Jiang cellular modelsand madecolleagues it possible using mouse to gain and further human insights cellular into mo thedels function made it ofpossible this retroposon. to gain further Mouse insights RPL10L showsinto about the function 99% identity of this in retroposon. the aminoacid Mouse sequence RPL10L comparedshows about to RPL1099%
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