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Paraspeckles: Possible Nuclear Hubs by the RNA for the RNA

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Paraspeckles: Possible Nuclear Hubs by the RNA for the RNA BioMol Concepts, Vol. 3 (2012), pp. 415–428 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/bmc-2012-0017 Review Paraspeckles: possible nuclear hubs by the RNA for the RNA Tetsuro Hirose 1, * and Shinichi Nakagawa 2 Introduction 1 Biomedicinal Information Research Center , National Institute of Advanced Industrial Science and Technology, The eukaryotic cell nucleus is highly compartmentalized. 2-4-7 Aomi, Koutou 135-0064, Tokyo , Japan More than 10 membraneless subnuclear organelles have 2 RNA Biology Laboratory , RIKEN Advanced Research been identifi ed (1, 2) . These so-called nuclear bodies exist Institute, 2-1 Hirosawa, Wako 351-0198 , Japan in the interchromosomal space, where they are enriched in multiple nuclear regulatory factors, such as transcription and * Corresponding author RNA-processing factors. These factors are thought to serve e-mail: [email protected] as specialized hubs for various nuclear events, including transcriptional regulation and RNA processing (3, 4) . Some nuclear bodies serve as sites for the biogenesis of macromo- Abstract lecular machineries, such as ribosomes and spliceosomes. Multiple cancer cell types show striking alterations in their The mammalian cell nucleus is a highly compartmental- nuclear body organization, including changes in the numbers, ized system in which multiple subnuclear structures, called shapes and sizes of certain nuclear bodies (5) . The structural nuclear bodies, exist in the nucleoplasmic spaces. Some of complexity and dynamics of nuclear bodies have been impli- the nuclear bodies contain specifi c long non-coding RNAs cated in the regulation of complex gene expression pathways (ncRNAs) as their components, and may serve as sites for in mammalian cells. long ncRNA functions that remain largely enigmatic. A Also known as the ‘ ribosome factory ’ , the nucleolus is the paraspeckle is a nuclear body that is almost ubiquitously classic nuclear body and the site at which RNA polymerase I observed in mammalian cultured cells but is cell population- transcription, pre-rRNA processing and modifi cation and sub- specifi c in adult mouse tissue. The paraspeckle structure is sequent ribosomal protein assembly occur sequentially within RNase-sensitive. Long ncRNAs, termed MEN ε / β ncRNAs the hierarchical structure of the nucleolus (6, 7) . (also referred to as NEAT1 ncRNAs), have been identi- Cajal bodies (CBs) were originally discovered in the fi ed as the RNA components of the paraspeckles. Specifi c nucleus of various cell types at the beginning of the 20 th cen- elimination has revealed that MEN ε / β ncRNAs are essential tury (8) . CBs are spherical suborganelles of 0.2 – 2.0 µ m in components for the formation of the intact paraspeckle struc- diameter that can be specifi cally marked by autoantibodies ture. Paraspeckle formation requires the continual MENε / β against p80/Coilin. They are involved in the biogenesis of ncRNA biogenesis process, including ongoing transcrip- multiple small nuclear ribonucleoprotein particles (snRNPs) tion, alternative 3′ -end processing, and stabilization. Some and small nucleolar ribonucleoprotein particles (snoRNPs) paraspeckle-localized RNA-binding proteins (p54/nrb and (9, 10) . CBs often overlap with distinct subnuclear structures PSF) direct paraspeckle formation through the selective sta- called histone locus bodies, in which histone gene clusters, bilization of MEN β ncRNA. Both MEN ε / β ncRNA expres- histone gene transcription factors and histone mRNA pro- sion and their subsequent interactions with paraspeckle cessing factors, such as NPAT and U7 snRNP, are localized proteins can be regulated under environmental and develop- (10, 11) . mental conditions, which are refl ected in the size and num- Gems are nuclear bodies that contain a large protein com- ber of the paraspeckles. However, how paraspeckles function plex, including the survival motor neuron (SMN) protein, and remains largely unsolved. Paraspeckles appear to serve as the often overlap with CBs (10, 12) . Although the SMN complex site of nuclear retention of specifi c mRNAs that are selec- is involved in the biogenesis of snRNPs in the cytoplasm, its tively transported to the cytoplasm upon certain signals. roles in nuclear gems are poorly understood. Alternatively, MENε / β ncRNAs may sequester paraspeckle The nuclei of various cell types each contain 25 – 50 irregu- proteins that function outside the paraspeckles. This review larly shaped nuclear structures, called nuclear speckles, of focuses on known aspects of paraspeckles and provides a 0.8 – 1.8 µ m in diameter. These structures are identical to model of their structure and function. the interchromatin granule clusters (IGS) seen by electron microscopy. The pre-mRNA splicing machinery, including Keywords: long non-coding RNA; nuclear body; small nuclear ribonucleoprotein particles (snRNPs), spli- paraspeckle; RNA-binding protein; RNA-protein interaction. ceosome subunits, and other non-snRNP protein splicing 416 T. Hirose and S. Nakagawa factors, shows a punctate nuclear localization pattern that is to distinct nuclear foci (Sam68 bodies) at the periphery of usually termed ‘ a speckled pattern ’ (13, 14) . In spite of the the nucleolus. Electron microscopic analysis has revealed accumulation of splicing factors in nuclear speckles, subse- that Sam68 bodies contain nucleic acids, presumably RNA. quent studies indicated that splicing generally does not occur The targeting of Sam68 to these nuclear bodies involves its in nuclear speckles. Currently, nuclear speckles are widely highly conserved RNA-binding domain (GSG domain) (35) . considered to be the reservoir of various splicing factors that Another splicing regulatory factor, polypyrimidine tract bind- are translocated to the transcriptionally active sites of the ing protein (PTB), colocalizes to a distinct perinucleolar com- chromosome (14) . partment (PNC) with several RNA polymerase III transcripts, Many nuclear bodies contain specifi c RNA molecules, including ribonuclease P RNA and RNase mitochondrial pro- including those that are unlikely to code for polypeptides, cessing (MRP) RNA (36) . Thus, many nuclear bodies contain so-called non-coding RNAs (ncRNAs). Genome-wide tran- specifi c ncRNA molecules and RNA-binding proteins and scriptomic analyses have revealed that numerous ncRNAs are may serve as platforms for the regulation of gene expression produced from multiple intergenic regions and various por- and ribonucleoprotein biogenesis, in addition to their func- tions of the human and mouse genomes (15 – 20) . Recently, tions as reservoirs. several abundant long ncRNAs were shown to localize to This review will focus on the structure and function of the specifi c nuclear bodies. This fi nding raised the intriguing pos- specifi c nuclear body called the paraspeckle, which is com- sibility that these nuclear bodies are sites where the ncRNAs prised of specifi c nuclear-retained long ncRNAs and multiple play certain regulatory roles in nuclear events, such as gene RNA-binding proteins. Recent research has uncovered the expression, the modulation of protein function or the biogen- unique architecture of the paraspeckle and the possible regula- esis of macromolecular machineries (21 – 25) . tory functions that are encoded by its abundant long ncRNAs. For instance, nuclear speckles contain the highly abun- The signifi cance of the ncRNAs in paraspeckle structural for- dant long ncRNA Malat-1 (also known as nuclear enrichment mation and its functional relevance are discussed, with con- abundant transcript 2 [NEAT2]) and unidentifi ed polyadeny- sideration of other recently reported nuclear RNA granules lated RNAs. Malat-1 is a nuclear ncRNA of ∼ 8 kb in size involved in stress response and diseases. that is signifi cantly associated with cancer metastasis (26, 27) . Malat-1 ncRNA reportedly regulates alternative splicing patterns by modulating the phosphorylation status of SR-rich The paraspeckle: its discovery and unusual splicing factors (28) and controls synaptogenesis by modu- features lating the expression of genes involved in this process (29) . Rosenfeld and colleagues reported that Malat-1 associates The paraspeckle was discovered in 2002 by the Angus Lamond with unmethylated Polycomb 2 (Pc2) in nuclear speckles, Laboratory at the University of Dundee, Scotland (37) . Because which leads to relocation of the target gene locus. This event these new nuclear bodies were localized in close proximity to triggers the SUMOylation of Pc2, which leads to activation nuclear speckles, they were named ‘ paraspeckles ’ . Initially, of the growth-control gene program (30) . By contrast, methy- Lamond and his colleagues performed large-scale proteomics lated Pc2 associates with TUG1 ncRNA, which specifi cally analyses of isolated HeLa cell nucleoli treated with the tran- localizes to Polycomb bodies (PcGs). This process leads to scription inhibitor actin omycin D, identifying 279 nucleolar the relocation and suppression of the above genes under qui- protein candidates. Among the functionally uncharacterized escent conditions (30) . Thus, it has been suggested that long proteins in the identifi ed nucleolar protein candidates, two ncRNAs in the nuclear bodies integrate the various regula- proteins, named paraspeckle proteins 1 and 2 (PSP1 and PSP2, tory events by sequestering and dissociating the key regula- respectively), exhibited nuclear punctate localization (37) . tory factors. Interestingly, PSP1 and PSP2 were not enriched in nucleoli Although the detailed
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