Circular RNA: metabolism, functions and interactions with proteins

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Dec. 1, 2020

Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges protein templates. Moreover, emerging evidence has revealed a group circRNAs can serve decoys, scaffolds recruiters. However, existing research on circRNA-protein interactions is quite limited. Hence, this review, we briefly summarize recent progress metabolism elaborately discuss patterns interactions, including altering between proteins, tethering or sequestering recruiting proteins chromatin, forming circRNA-protein-mRNA ternary complexes translocating redistributing proteins. Many discoveries unique expression signatures play crucial roles variety diseases, enabling them potentially act diagnostic biomarkers therapeutic targets. This review systematically evaluates mechanisms circRNAs, with hope advancing translational medicine involving

Language: Английский

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Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

Cell, Journal Year: 2019, Volume and Issue: 179(4), P. 964 - 983.e31

Published: Oct. 1, 2019

To elucidate the deregulated functional modules that drive clear cell renal carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration proteogenomic measurements uniquely protein dysregulation cellular mechanisms impacted by alterations, including oxidative phosphorylation-related metabolism, translation processes, phospho-signaling modules. assess degree immune infiltration in individual tumors, microenvironment signatures delineated four immune-based subtypes characterized pathways. This study reports large-scale analysis to discern impact alterations provides evidence for rational treatment selection stemming from pathobiology.

Language: Английский

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The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112

Nucleic Acids Research, Journal Year: 2019, Volume and Issue: 47(15), P. 7719 - 7733

Published: July 12, 2019

Abstract N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have described functionally structurally, but the enzymes responsible for installing one residue each subunit human ribosomes at sites eluded identification over 30 years. Here, we identify METTL5 as enzyme 18S rRNA modification confirm ZCCHC4 28S enzyme. We show that must form a heterodimeric complex with TRMT112, known methyltransferase activator, gain metabolic stability in cells. provide first atomic resolution structure METTL5–TRMT112, supporting its RNA-binding mode differs distinctly from other methyltransferases. On basis similarities DNA methyltransferase, propose METTL5–TRMT112 acts by extruding adenosine be modified double-stranded nucleic acid.

Language: Английский

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Proteogenomic Characterization of Endometrial Carcinoma

Cell, Journal Year: 2020, Volume and Issue: 180(4), P. 729 - 748.e26

Published: Feb. 1, 2020

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences perturbations to the p53 Wnt/β-catenin pathways, identified potential role for circRNAs in epithelial-mesenchymal transition, provided information about proteomic markers clinical genomic tumor subgroups, including relationships known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling histone acetylation. also characterized aspects immune landscape, immunogenic alterations, neoantigens, common cancer/testis antigens, microenvironment, all which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide valuable resource researchers clinicians, identify molecular associations mechanistic significance development cancers, suggest novel approaches identifying therapeutic targets.

Language: Английский

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Eukaryotic Ribosome Assembly

Annual Review of Biochemistry, Journal Year: 2018, Volume and Issue: 88(1), P. 281 - 306

Published: Dec. 19, 2018

Ribosomes, which synthesize the proteins of a cell, comprise ribosomal RNA and proteins, coassemble hierarchically during process termed ribosome biogenesis. Historically, biochemical molecular biology approaches have revealed how preribosomal particles form mature in consecutive steps, starting nucleolus terminating after nuclear export into cytoplasm. However, only recently, due to revolution cryo-electron microscopy, could pseudoatomic structures different be obtained. Together with vitro maturation assays, these findings shed light on nascent ribosomes progress stepwise along dynamic biogenesis pathway. Preribosomes assemble gradually, chaperoned by myriad assembly factors small nucleolar RNAs, before they reach maturity enter translation. This information will lead better understanding synthesis is linked other cellular pathways humans it can cause diseases, including cancer, if disturbed.

Language: Английский

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Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis

Science, Journal Year: 2020, Volume and Issue: 367(6485), P. 1468 - 1473

Published: Feb. 7, 2020

Metastasis: A matter of translation? Solid tumors shed a small number cancer cells into the bloodstream, some which are believed to contribute metastasis. The molecular features that confer these circulating tumor (CTCs) with metastatic potential poorly understood. Ebright et al. studied CTCs from breast patients and found increased expression levels certain ribosomal proteins regulators translation had greater capacity in mouse model (see Perspective by Ma Jeffrey). Consistent this finding, higher subset tended have poorer prognosis. Science , issue p. 1468 ; see also 1424

Language: Английский

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Molecular logic of mTORC1 signalling as a metabolic rheostat

Nature Metabolism, Journal Year: 2019, Volume and Issue: 1(3), P. 321 - 333

Published: March 4, 2019

Language: Английский

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Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 30, 2021

Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth proliferation. The ribosomal proteins (RPs), comprising the structural parts of ribosome, essential ribosome assembly function. In addition to their canonical functions, multiple RPs have extra-ribosomal functions including activation p53-dependent or p53-independent pathways in response stress, resulting cycle arrest apoptosis. Defects biogenesis, translation, individual RPs, mutations been linked a diverse range human congenital disorders termed ribosomopathies. Ribosomopathies characterized by tissue-specific phenotypic abnormalities higher cancer risk later life. Recent discoveries somatic tumor types reinforce connections between defects cancer. this article, we review most recent advances understanding molecular consequences RP ribosomopathies We particularly discuss basis transition from hypo- hyper-proliferation with elevated risk, paradox "Dameshek's riddle." Furthermore, current treatments prospective therapies targeting defects. also highlight stress-based therapeutics. Importantly, insights into mechanisms resistance bring new perspectives susceptibility clinical implications therapy.

Language: Английский

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Identification of cancer driver genes based on nucleotide context

Nature Genetics, Journal Year: 2020, Volume and Issue: 52(2), P. 208 - 218

Published: Feb. 1, 2020

Language: Английский

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Uncovering the assembly pathway of human ribosomes and its emerging links to disease

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(13)

Published: May 14, 2019

Review14 May 2019Open Access Uncovering the assembly pathway of human ribosomes and its emerging links to disease Katherine E Bohnsack Corresponding Author [email protected] orcid.org/0000-0001-6035-4255 Department Molecular Biology, University Medical Center Göttingen, Germany Search for more papers by this author Markus T orcid.org/0000-0001-7063-5456 Göttingen Biosciences, Georg-August University, Information *,1 *,1,2 1Department 2Göttingen *Corresponding author. Tel: +49 551 395978; Fax: 395960; E-mail: 395968; The EMBO Journal (2019)38:e100278https://doi.org/10.15252/embj.2018100278 See Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract essential cellular process ribosome biogenesis is at nexus various signalling pathways that coordinate protein synthesis with growth proliferation. fact numerous diseases are caused defects underscores importance obtaining a detailed understanding pathway. Studies yeast have provided wealth information about fundamental principles assembly, although many features conserved throughout eukaryotes, larger size (pre-)ribosomes, as well evolution additional regulatory networks can modulate function, resulted complex humans. Notably, factors from appear subtly different or functions In addition, recent genome-wide, RNAi-based screens identified plethora novel required biogenesis. review, we discuss key aspects production, highlighting differences yeast, disease, concepts such extra-ribosomal ribosomal proteins heterogeneity. cryo-EM cryo-electron microscopy DBA Diamond-Blackfan anemia ETS external transcribed spacer IRES internal entry site ITS LSU large subunit Nm ribose 2′-O-methylation NTP nucleoside triphosphate RBF factor RNP ribonucleoprotein RP snoRNP small nucleolar SSU UTR untranslated region Ψ pseudouridine Ribosome production: going beyond model system Production an carried out ribosomes, which complexes (RNPs) composed four RNAs (rRNAs; 18S, 5S, 5.8S 25S (yeast)/28S (humans)) approximately 80 (RPs) (Ben-Shem et al, 2010; Anger 2013). requires coordinated action all three RNA polymerases one most energy-consuming processes, 7,500 new subunits synthesised per minute actively growing HeLa cells (Warner, 1999; Lewis Tollervey, 2000). begins nucleolus polymerase I-mediated rRNAs single precursor rRNA (pre-rRNA) transcript. Recruitment RPs trans-acting (RBFs) nascent transcript leads formation large, early pre-ribosomal particles (90S). Concurrent pre-rRNA extensively processed modifications take place. A central cleavage event gives rise precursors (SSU; 40S) (LSU; 60S) subunits. pre-40S pre-60S undergo extensive structural remodelling, involving dynamic association dissociation RBFs establishment structures. After immature independently exported cytoplasm, final maturation quality control steps occur before they engage translation. Eukaryotic best characterised organism Saccharomyces cerevisiae (budding yeast; Woolford Baserga, While basic among has evolved be considerably due increased pre-ribosomes, function. Proteomic analyses nucleoli several (Andersen 2002; Scherl Wild Tafforeau 2013; Badertscher 2015; Farley-Barnes 2018) facilitated identification RBFs, characterisation some these already highlighted interesting between ribosomes. Furthermore, revealed extent other processes. uncovering gaining comprehensive humans underscored increasing number genetic (ribosomopathies) been found mutations genes encoding (Narla Ebert, Mills Green, 2017). expanding body evidence demonstrates regulated oncogenic pathways, turn linked activation tumour suppressors including p53 (Pelletier 2018). Here, review current knowledge humans, focusing on detail, yeast. We further highlight topics heterogeneity, describe regulation how disease. Identification properties list 200 compiled over years based mass spectrometric isolated examination effects depletion production (Woolford inventory provides excellent basis analysing than 4,500 detected 2002), implying may contribute cells. To identify cells, RNAi-based, high-throughput recently performed (Wild pioneering microscopy-based screen monitoring mis-localisation confirmed involvement 153 2010), approach was subsequently extended genome-wide level, revealing 300 40S (Badertscher 2015). Concurrently, 286 74 without homologues, were whose affects processing (Tafforeau 139 potential discovered affecting morphology (Farley-Barnes These screens, together studies characterising individual subsets not only homologues but also significant emphasising correct homeostasis. Some now analysed newly still lack functional characterisation, their precise roles unknown. Although biogenesis, it unlikely bona fide components complexes, observed rather point mechanisms regulated. For example, alongside anticipated involved transcription, pre-mRNA splicing translation 2015), probably indicating crosstalk gene expression metabolic enzymes 2018), suggesting co-ordination nutrient availability cell growth; line high energy demands production. Depleting degradation machineries maintaining levels important ongoing future, will therefore clearly differentiate directly proteins/pathways inventories RFBs diversity maturation. As primarily mediate protein–protein interactions act scaffolds, while others RNA-binding proteins, possess catalytic activity. spectrum enzymatic includes nucleases, modification kinases (discussed detail below), (NTP)-dependent GTPases, AAA-ATPases helicases remodelling events. Six active GTPases (Nog1, Nog2, Nug1, Bms1, Lsg1, Efl1) each none those so far. Three (Rea1/Mdn1, Rix7, Drg1) implicated triggering release specific (reviewed Kressler 2012), (MDN1, NVL2 AFGH2, respectively) known. case MDN1, PELP1-TEX10-WDR18 (Rix1 yeast) suggest function enzyme (Raman 2016). Human nuclear exosome telomerase (Her Chung, 2012; Yoshikatsu multifunctional biology. common (e.g. Dhr1 DHX37 both U3 snoRNA; Martin Sardana Choudhury 2019), described helicases. Examples include requirement DDX51 metazoan-specific snoRNA U8 pre-LSU (Srivastava DDX21 coupling transcription processing, facilitating access late-acting (snoRNPs) (Calo Sloan events catalysed often serve checkpoints during thereby help maintain directionality associate independently, hallmark eukaryotic modular complexes. UTP-A, UTP-B UTP-C snoRNP, RCL1-BMS1 heterodimer IMP3-IMP4-MPP10 EMG1 recruited form core so-called "SSU processome" (see Table 1 references therein). Similarly, sub-complexes, PeBoW (Nop7-Erb1-Ytm1 (Rix1-Ipi3-Ipi1 Despite evolutionary conservation composition varies species, (Table 1). DDX27, respectively (Kellner helicases, possibly need stages pre-ribosome compared sub-complexes apoptosis-antagonising AATF, neuroguidin (NGDN) NOL10 sub-complex (ANN) co-stabilise (Bammert any ANN XND, another G-patch NF-κB-repressing (NKRF), helicase DHX15 5′-3′ exonuclease XRN2, (Memet XRN2 NKRF where fulfils turnover excised fragments. stimulates ATPase unwinding activity 2017), suggested step facilitates initial cleavage. 5′ (ETS) contrasts homologue Prp43, snoRNAs 3′ end 18S cytoplasm (Bohnsack 2009; Pertschy 2009). NF45-NF90 heterodimer, initially binding interleukin-2 promoter, component (Wandrey interaction shown mediated double-stranded domains (dsRBDs) NF90, direct rRNA. no clear defect upon either NF45 causes changes accumulation nucleoplasm, confirming 1. Composition Complex Refs. Yeast UTP-A Utp4 UTP4 (Cirhin) Krogan al (2004), Prieto McStay (2007), Freed (2012) Utp5 UTP5 (WDR43) Utp8 – Utp9 Utp10 UTP10 (BAP28) Utp15 UTP15 Utp17 UTP17 (WDR75) NOL11 Utp1 PWP2 (2015) Utp6 UTP6 Utp12 UTP12 Utp13 TBL3 Utp18 UTP18 Utp21 WDR36 NOP2 Rrp7 RRP7A Gérus (2010), Baudin-Baillieu (1997) Utp22 NOL6 Cka1 CSNK2A1 Cka2 Ckb1 CSNK2B Ckb2 Rrp36 RRP36 Grandi (2002), Turner Nop56 NOP56 Nop58 NOP58 Snu13 15.5K Nop1 Fibrillarin Rrp9 U3-55K IMP3-IMP4 Imp3 IMP3 Granneman (2003) Imp4 IMP4 Mpp10 MPHOSPH10 Rcl1 RCL1 Wegierski (2001), Wang (2016) Bms1 BMS1 Emg1 Liu Thiele Kühn (2009), Warda Nop14 NOP14 Noc4 NOC4L UTP14A Nop7 PES1 Holzel (2005), Rohrmoser Kellner Erb1 BOP1 Ytm1 WDR12 DDX27 Rix1 PELP1 Finkbeiner (2011a,b) Ipi3 TEX10 Ipi1 WDR18 XND Memet (2017) AATF Bammert NGDN Wandrey NF90 Specialisation higher eukaryotes An aspect studied emerged Maturation removal spacers (ETS ITS, respectively), up five times longer combination endonucleolytic exonucleolytic (Henras Tomecki ITS1 largely co-transcriptionally majority appears post-transcriptionally (Lazdins 1997). Analogous sites pre-rRNAs. Several indicate corresponding endonucleases (Utp24/UTP24, Nob1/NOB1, RNase MRP, Las1/LAS1) (Figure 1), there notable exceptions (Schmitt Clayton, 1993; Fatica 2003; Preti 2013a; Gasse Wells 2016; Goldfarb Cech, B0 cleaved Rnt1, homologous III does support role analogous 02 endonuclease(s) responsible A0 (yeast) (human) remain unknown, putative PIN-domain endonuclease UTP23, unlike degenerate counterpart retains amino acids typically (Wells additional, ETS, termed 01 A', far orthologues prevent site. Therefore, hitherto unidentified yet clear, mechanism (Wang Pestov, 2011; 2014). Serial cleavages within fragments degraded exonucleases (Schillewaert 2013a, 2014; 2017; Kobyłecki recycling bound RBFs. cases, mature ends formed UTP24 NOB1, respectively; Bai 2016), sequences followed processing. step-wise 3′-5′ Henras Different exonuclease, ISG2OL2, (Coute 2008). Also, trimming Ngl2 ERI1 (Faber Ansel striking contrast separates 3′-end Nob1, play removing Site 2 MRP sequential containing RRP6 poly(A)-specific ribonuclease PARN (Sloan Ishikawa Montellese Moreover, oligouridylated forms 3′-extended terminal uridylyltransferases (TUTases) likely (Montellese Pre-rRNA utilisation exo- aberrant pre-ribosomes. It remains unclear processive ensure regions. However, tempting speculate presence assembled secondary structures normally arrests appropriate position, poised efficiently degrade incorrectly pre-ribosomes assembly. Figure cellsSchematic views primary transcripts (35S, upper panel) (47S, lower scale. Mature 25S/28S indicated black rectangles, (5′-ETS 3′-ETS) (ITS1 ITS2) represented lines. Relative positions indicated, specified below transcripts. Enzymes (Endonucleases—red; exonucleases—blue; enzymes—grey; unknown enzymes—?). Download figure PowerPoint Analyses that, strict hierarchical order, alternative routes generate initiated subsequent place A2 (approximately 85% pre-rRNAs) A3 15% pre-rRNAs; Schmitt 1993). prominent orders. This flexibility order cleavages, differing kinetics events, variations steady-state intermediates organisms types. relevance unclear. possible having diverse simply ensures robustness greater means regulate Comparison universally feature chemically modified residues centres ribosome, peptidyl transfer centre, decoding intersubunit interface (Decatur Fournier, Polikanov collectively stability structure regulating Mapping 112 228 sites, respectively, analysis enabled visualisation situ 2; Ofengand Bakin, 1997; Piekna-Przybylska 2008; Carlile Krogh Taoka 2016, 2018; Natchiar present 2′-O-methylations moieties (Nm) pseudouridylations (Ψ), introduced box C/D H/ACA snoRNPs, (Watkins Bohnsack, 2012). guiding computationally predicted (Lestrade Weber, 2006; Gumienny predictions experimental confirmation non-snoRNP-dependent (Gm2922) Sbp1 (Lapeyre Purushothaman, 2004), notably, FTSJ3 maturation, distinct (Morello 2011). Due basepairing substrates, snoRNA-guided expected installed when open, whether determined. total bases exceeds twofold (Piekna-Przybylska density arises reflects fine-tuning see below). 2. Distribution rRNAsTertiary (SSU) PBD 4V6X) shown, depicted ribbons surface view. type nucleotide position base modifications, regions indicated. Of note, (Jorjani guide species U6 snRNA mRNAs (Aw Sharma Sloan, types 18S-ac4C1842 SNORD13; Cavaille 1996; Ito 2017b), some, (SNORD3), U14A/B (SNORD14A/B), U17A/B (SNORA73A/B) (SNORD118) U22 (SNORD22), pre-RNA folding forming distant (Savino Gerbi, 1990; Peculis Steitz, Tycowski 1994; Mishra Eliceiri, Dunbar 1998). uncovered; HBII-52 (SNORD115) regulates serotonin receptor 2C pre-mRNA, SNORD86 modulates dictating usage splice (Kishore Stamm, Lykke-Andersen Other cognate methyltransferases except two N3-methyluridines (m3Us) 25S-U2634 25S-U2843 rRNA, neither 28S 2)

Language: Английский

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