Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Deep Insight Section Y RNA in cell cycle progression and cancer Roberto Piergentili Department of Biology and Biotecnology - Charles Darwin, Sapienza University of Rome - Istituto Genetica, room 1-07 - P.Le A.Moro 5 00185 Roma, Italy [email protected] Published in Atlas Database: February 2020 Online updated version : http://AtlasGeneticsOncology.org/Deep/YRNAID20152.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70820/02-2020-YRNAID20152.pdf DOI: 10.4267/2042/70820 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology erythematosus, (iii) neonatal lupus erythematosus, Abstract (iv) ANA-negative lupus erythematosus, and (v) systemic lupus erythematosus-like disease. These A growing amount of evidence demonstrates the role diseases are characterized by having as autoantigen of non-coding RNAs (ncRNA) in the targets, among the others, the soluble etiopathogenesis of cancer. ncRNA are the product ribonucleoproteins (RNP) (also known as SSA or of the transcription of genes which are not further TROVE2 - TROVE domain family, member 2) translated into proteins, thus they exert their (Deutscher et al. 1988; Ben-Chetrit et al. 1989) and functions as they are or more frequently after post- (small RNA-binding exonuclease protection factor - transcriptional modifications. In the last decades, also known as La) (Chambers et al. 1988). Y RNA several different classes of ncRNA had been are small non-coding RNAs that were originally described, both long (lncRNA) and short (sncRNA). identified as the RNA component of RO60 and SSB The former are molecules usually longer than 200 in these patients (Lerner et al. 1981; Hendrick et al. nucleotides (nt), while the latter usually include 1981). Y RNA, like other small RNAs, are species of a few tens of nucleotides in length, transcribed by RNA Polymerase III (Pol III) although exceptions are present (for example, (Hendrick et al. 1981; Wolin and Steitz 1983). After circRNA span a length of 100-1600nt; snoRNA are transcription, they may either remain inside the 60-300nt). Y RNA belong to the sncRNA family and nucleus or be exported in the cytoplasm (Kowalski are in the range of ca. 80-120nt. Here we summarize and Krude 2015). They were originally termed as 'Y' the current knowledge about Y RNA biology, their RNA to distinguish their cytoplasmic localization role in normal cellular homeostasis, and their from that of the nuclear 'U' RNA (Lerner et al. 1981). expression variations in human cancers. There are four known Y RNA members in humans, Keywords named hY1 (length: 112 nucleotides, nt), hY3 hY1; hY3; hY4; hY5; RNY1; RNY3, RNY4; RNY5; (101nt), hY4 (93nt) and hY5 (83nt) RNA; the cell cycle; DNA replication; RO60; presence of hY2 RNA was later confuted, as it was ribonucleoprotein particle found that it is a degradation product of hY1. Discovery, evolutionary According to ENSEMBL 75, there are also an additional 52 transcripts which are pseudogenes conservation and structure based on the 4 human Y RNA, and a further 966 The first discovery of Y RNA (Lerner et al. 1981) hYRNA pseudogenes (Perreault et al. 2005), with has been made by immunopurification with auto- 878 predicted transcripts, that make up the Y RNA antibodies in patients affected by the autoimmune category. In the most common use, hY1-5 are the diseases systemic lupus erythematosus (SLE) and names of the RNAs, while the HGNC approved gene subsequently confirmed in (i) primary Sjogren symbol for the four genes are RNY1-5, respectively syndrome, (ii) subacute cutaneous lupus (i.e. , , and ). Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10) 379 Y RNA in cell cycle progression and cancer Piergentili R Figure 1: structure of a generic human Y RNA. For the structure of specific genes, please see for example (Köhn et al. 2013); note that the loop domain is the less conserved both in length and structure, among all studied organisms and among the four human RNAs. Image taken from the Rfam database release 9.1 (http://rfam.xfam.org/family/RF00019) and partially modified (picture rotation; indication of domains). Nucleotide coloring indicates sequence conservation between the members of this family. Y RNA have two recognized functions: repressors of significantly among the four hY RNA: it is likely RO60 and other Ro proteins, and initiation factors very flexible (Teunissen 2000) and fulfills different for DNA replication (Christov et al. 2006; Zhang et tasks such as modulation of chromatin association, al. 2011; Hall et al. 2013). Y RNA are conserved protein binding site (such as those reported in Table molecules, and confirmed (true Y RNA) or putative 1) (Fabini et al. 2001; Fouraux et al. 2002; Belisova (stem-bulge RNAs, sbRNA (Boria et al. 2010)) et al. 2005; Hogg and Collins 2007; Gallois- members of this family are found in mammals, birds, Montbrun et al. 2008; Sim et al. 2012; Köhn et al. amphibians, fishes, worms, insects, tunicates and 2013, 2015; Shukla and Parker 2017; Donovan et al. even bacteria (Mosig et al. 2007; Perreault et al. 2017) and site of cleavage for the formation of 2007; Boria et al. 2010; Duarte Junior et al. 2015, YsRNA (Y RNA-derived small RNAs, stretches of 2019). However, in some lower organisms such as 22-36 nucleotides that are produced in apoptotic Caenorhabditis elegans (CeY RNA), Branchiostoma cells - see the specific section below) (van Gelder et floridae (BfY RNA) and Deinococcus radiodurans al. 1994; Teunissen 2000; Kowalski and Krude (DrY RNA) the sequence similarity to vertebrate Y 2015). It is expected that Y RNA contemporarily RNA is only partial and does not include the upper bind at least two proteins, one of which is a core stem domain (Gardiner et al. 2009); moreover, their protein bound on the stem domain (such as RO60) function is not essential in them, since mutant and another on the loop domain; indeed, experiments organisms with missing Y RNA are viable. To date, using gel filtration show that Y RNP range in size only plants and fungi do not have any candidate Y from 150 to 550 kDa (see (Köhn et al. 2013) and RNA or sbRNA, thus the evolution of these references therein). All human Y RNA genes map molecules is still a debated topic in eukaryotes. inside the region 7q36.1 (Maraia et al. 1994; Maraia The stem-loop organization of Y RNA is conserved 1996) and, in particular, RNY3 is on the opposing as well, and it is schematically reported in Figure 1. DNA strand from the gene RNY1 (Wolin and Steitz Four specific regions can be identified. (i) A poly- 1983); interestingly, despite their high homology, uridine tail that is important for SSB binding and for these two RNAs do not cross-hybridize (Wolin and Y RNA stabilization (target of exonucleases); Steitz 1983). This clustering of Y RNA coding genes moreover, some authors suggest that, at least hY1 on chromosomes has been described also in other and hY3, potentially contain a variety of 3' ends, vertebrates (O'Brien et al. 1993; Farris et al. 1996; with the most abundant species being at positions -5 Mosig et al. 2007). and -4 relative to the previously mapped 3' ends Role of Y RNA in RO60 function (Shukla and Parker 2017). (ii) A lower stem domain, which is the binding site of RO60 and is important Ro ribonucleoproteins (Ro RNP) are implicated in for nuclear export; this region is frequently flanked RNA processing and quality control (Hogg and by a bulged region that is essential for RO60 binding Collins 2007; Sim and Wolin 2011), as well as in and separates the lower stem from (iii) an upper stem intracellular transport, bringing other Y RNA domain, which is important for the initiation of DNA binding proteins to their specific targets (Belisova et replication. Finally, (iv) a loop domain, which is the al. 2005). It has been recently proposed that an most variable portion of the Y RNA. In particular, evolutionarily conserved function of non-coding the loop domain length and sequence are the most RNAs (ncRNA), including Y RNA, might be the discriminating parameters among the four human Y assembly and function of RNP complexes; in this RNA, the longest loop being that of hY1 (65 nt) and case, these molecules could act as scaffolding factors the shortest that of hY5 (31 nt). Also the three- necessary to form functional RNP (Täuber et al. dimensional folded structure of the loops differ 2019). Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10) 380 Y RNA in cell cycle progression and cancer Piergentili R Protein (HGNC) Synonyms Interacting Y RNA Domain involved Function CEM15 1, 3, 4, 5 unknown unknown NEB1 1, 3 loop histone pre-mRNA processing EXOSC11 (1), (3) polyU tail Y RNA stabilization DIS3L1 1, 3 polyU tail Y RNA degradation and turnover PMSCL2 1, 3, 4, 5 polyU tail Y RNA trimming, stabilization HNRPK 1, 3 loop unknown C20ORF183 (1), 3 loop nuclear Export of RO60 and Y3 nucleolin, C23 1, 3 loop unknown DAN 1, 3, 4, 5 polyU tail Y RNA trimming, stabilization hnRNP I, PTB 1, 3 loop unknown RoBP1, FIR (1), (3), 5 unknown unknown PRCA1, RNS4 1, (3), 4, 5 loop cell cycle arrest and apoptosis La, LARP3 1, 3, 4, 5 polyU tail nuclear localization, protection of Y RNA 3' ends PAPD5 1, 3, 4, 5 polyU tail Y RNA oligoadenylation, degradation PCH7 1, (3) polyU tail Y RNA degradation and turnover TROVE2, Ro60, SSA 1, 3, 4, 5 lower stem stabilization, nuclear export, RNA quality control Table 1 - Y RNA binding proteins.