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Paraspeckles Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Paraspeckles Archa H. Fox1 and Angus I. Lamond2 1Western Australian Institute for Medical Research and Centre For Medical Research, University of Western Australia, Crawley 6009 Western Australia, Australia 2Wellcome Trust Centre for Gene Regulation & Expression, College of Life Sciences, University of Dundee DUNDEE DD1 5EH UK Correspondence: [email protected] Paraspeckles are a relatively new class of subnuclear bodies found in the interchromatin space of mammalian cells. They are RNA-protein structures formed by the interaction between a long nonprotein-coding RNA species, NEAT1/Men 1/b, and members of the DBHS (Drosophila Behavior Human Splicing) family of proteins: P54NRB/NONO, PSPC1, and PSF/SFPQ. Paraspeckles are critical to the control of gene expression through the nuclear retention of RNA containing double-stranded RNA regions that have been subject to adenosine-to-inosine editing. Through this mechanism paraspeckles and their components may ultimately have a role in controlling gene expression during many cellular processes including differentiation, viral infection, and stress responses. DISCOVERY OF PARASPECKLES human nucleoli, 271 proteins were identified, he cell nucleus is a large and complex cellu- 30% of which were novel (Andersen et al. Tlar organelle with an intricate internal or- 2002). A follow up analysis on one of these ganization that is still not fully characterized. newly identified novel proteins, showed that it One feature of nuclear organization is the was not enriched in nucleoli, but instead was presence of distinct subnuclear bodies, each of found diffusely distributed within the nucleo- which contain specific nuclear proteins and plasm as well as concentrated in 5–20 sub- nucleic acids (Platani and Lamond 2004). nuclear foci (Fox et al. 2002). Colocalization Most subnuclear bodies reside in the interchro- studies showed that these foci neither coin- matin space, including Cajal bodies, PML cided, nor directly overlapped, with markers bodies, and nuclear speckles, enriched in splic- for any previously known subnuclear structure. ing factors (Lamond and Spector 2003). The foci were thus named “paraspeckles” be- Paraspeckles are one of the most recent sub- cause they were observed in the interchromatin nuclear bodies identified, discovered in 2002 as space near to, yet distinct from, nuclear speck- part of a study to better understand the full les (Fig. 1). The novel protein that localized to biological role of the nucleolus. In a mass spec- these structures was subsequently named “Para- trometry based proteomic analysis of purified speckle Protein 1” (PSPC1). Editors: Tom Misteli and David Spector Additional Perspectives on The Nucleus available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a000687 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a000687 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press A.H. Fox and A. Lamond A B C D DBHS sequence conservation Protein–protein interaction P54NRB RRM1 RRM2 NOPS Coiled coil PSF RRM1 RRM2 NOPS Coiled coil PSPC1 RRM1 RRM2 NOPS Coiled coil Minimal region of PSPC1 needed for paraspeckle targeting Figure 1. Paraspeckles seen with fluorescent and electron microscopy. (A) Combined DIC and fluorescence micrograph of a HeLa cell stained with anti-PSPC1 to show paraspeckles (green) and B23 nucleolar marker (red). (B) Fluorescence micrograph of a section through a HeLa cell stained with anti-PSPC1 (green), anti-SC35 (red), and DAPI (blue) to show the relationship between paraspeckles and nuclear speckles. (C) Transmission electron micrograph of sections of HeLa cells immuno-gold labelled with anti-PSPC1: image kindly provided by Sylvie Souquere and Gerard Pierron (Villejuif, France). Scale bars in A–B, 10 mm, scale bar in C, 0.5 mm. (D) The DBHS protein family showing domain structure and indicating regions involved in paraspeckle biology. Considering that PSPC1 was first identified their steady-state enrichment within paraspe- in a proteomic screen for nucleolar factors, it ckles, explaining their presence in the nucleolar was initially surprising that localization studies proteome (Fox et al. 2002). did not detect it accumulated in nucleoli. How- ever, exploring the dynamic nature of PSPC1 PARASPECKLE CHARACTERIZATION revealed its nucleolar relationship. When cells were treated with drugs that inhibit RNA Poly- Paraspeckles are small, irregularly sized, and merase II (Pol II) transcription, PSPC1 relocal- unevenly distributed subnuclear bodies. De- ized to perinucleolar cap structures (Fox et al. pending on the cell type, paraspeckles number 2002 and Fig. 2). Perinucleolar enrichment of between 5 and 20 foci per nucleus (for example, PSPC1 was also observed in newly divided cells HeLa contain 13–17 foci/nucleus and NIH3T3 that had not recommenced transcription fol- 5–10 foci/nucleus, Clemson et al. 2009). lowing cell division (Fox et al. 2005). Thus EM studies and fluorescent images show a para- PSPC1 is found in paraspeckles in transcrip- speckle size range of 0.5–1 mm in diameter, and tionally active cells, and perinucleolar caps in they have an irregular, sausagelike shape (Cardi- cells that are not actively transcribing Pol II nale et al. 2007 and Fig. 1C). Transmission EM genes. Further, photodynamic studies showed of cells labeled with paraspeckle markers show that under normal conditions PSPC1 molecules labeling of distinct nuclear structures, rich in continually traffic through nucleoli, despite RNA (Prasanth et al. 2005; Cardinale et al. 2 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a000687 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Paraspeckles Thus far, paraspeckles are only evident in A mammalian nuclei. Within mammalian tissues Nucleolus Peri-nucleolar caps and cells, paraspeckles are wide-spread: The majority of mouse and human cell lines and tissues examined contain paraspeckles, includ- ing transformed and primary cell lines, embry- onic fibroblasts, and tumorigenic biopsies (Fox et al. 2002; Prasanth et al. 2005; Clemson et al. 2009; Sasaki et al. 2009; Sunwoo et al. 2009 and unpublished data). Interestingly, human embryonic stem cells (hESC) are so far the only mammalian cell type that are reported not to contain paraspeckles (Chen and Carmichael, B Contain fibrillarin, 2009). Orthologs of the core paraspeckle pro- p80coilin, tein components are found in other vertebrate Pol I factors and invertebrate species, however, a noncoding RNA (ncRNA) NEAT1, which is essential for paraspeckle formation (see below) is specific Contain Nucleolar body to mammals, likely explaining the restriction paraspeckle proteins and of paraspeckles to this class. other Pol II Paraspeckles are observed within the inter- factors chromatin space, sandwiched between larger nuclear speckles and chromatin. Current evi- dence suggests paraspeckles do not directly Figure 2. Perinucleolar caps observed with RNA Pol overlap with sites of active transcription, as II transcription inhibition. (A) Combined DIC and they do not contain newly made pulse-labeled fluorescence micrograph of HeLa cells following 4 h Br-UTP containing transcripts, however para- treatment with Actinomycin D to inhibit RNA Pol II transcription. Nucleolar morphology changes speckles may still form in association with some under these conditions, to create a nucleolar body active genes (see below) (Fox et al. 2002; Xie and a number of perinucleolar caps (arrow). Cells et al. 2006). Quantitation of staining on ultra- were transfected with a plasmid expressing thin sections of labeled cells shows that para- YFP-PSPC1 (green), that localizes to perinucleolar speckles contain inactive RNA Polymerase II caps under these conditions (large arrow); scale bar, (Pol II), whereas the newly made RNA and 5 mm. (B) Perinucleolar caps form upon inhibition active RNA Pol II reside on the edge of para- of RNA Pol II transcription, see text and (Shav-tal et al. 2005). speckles (Xie et al. 2006). The functional relationship between para- speckles and the nucleolus is yet to be fully elucidated, but the observed cycling of PSPC1 2007, Fig. 1C). These EM structures labeled with between paraspeckles and nucleoli, and the local- paraspeckle markers correspond, at least partly, ization of paraspeckle proteins to perinucleolar to the Interchromatin Granule Associated caps when RNA Pol II transcription is inhibited, Zones (IGAZ – Visa et al. 1993). IGAZ are elec- suggests that it may mediate some form of reg- tron dense fibrillar regions closely aligned to ulatory cross talk. Many other proteins involved interchromatin granules (nuclear speckles) in Pol II transcription are also observed within with unknown function. IGAZ are reported to perinucleolar caps in cells where Pol II tran- contain both U1 RNA and coilin, although scription is inactive (Shav-Talet al. 2005). These there is no evidence of colocalization between proteins appear to segregate into distinct cap paraspeckles and either of these molecules at structures: large “dark” perinucleolar caps the level of fluorescence (Fox et al. 2002). containing the paraspeckle proteins, as well as Cite this article as Cold Spring Harb Perspect Biol 2010;2:a000687 3 Downloaded from http://cshperspectives.cshlp.org/
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