Academic literature on the topic 'Nuclear speckles domain'
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Journal articles on the topic "Nuclear speckles domain"
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Xie, Sheila Q., Sonya Martin, Pascale V. Guillot, David L. Bentley, and Ana Pombo. "Splicing Speckles Are Not Reservoirs of RNA Polymerase II, but Contain an Inactive Form, Phosphorylated on Serine2 Residues of the C-Terminal Domain." Molecular Biology of the Cell 17, no. 4 (April 2006): 1723–33. http://dx.doi.org/10.1091/mbc.e05-08-0726.
Full textAbstract:
“Splicing speckles” are major nuclear domains rich in components of the splicing machinery and polyA+ RNA. Although speckles contain little detectable transcriptional activity, they are found preferentially associated with specific mRNA-coding genes and gene-rich R bands, and they accumulate some unspliced pre-mRNAs. RNA polymerase II transcribes mRNAs and is required for splicing, with some reports suggesting that the inactive complexes are stored in splicing speckles. Using ultrathin cryosections to improve optical resolution and preserve nuclear structure, we find that all forms of polymerase II are present, but not enriched, within speckles. Inhibition of polymerase activity shows that speckles do not act as major storage sites for inactive polymerase II complexes but that they contain a stable pool of polymerase II phosphorylated on serine2 residues of the C-terminal domain, which is transcriptionally inactive and may have roles in spliceosome assembly or posttranscriptional splicing of pre-mRNAs. Paraspeckle domains lie adjacent to speckles, but little is known about their protein content or putative roles in the expression of the speckle-associated genes. We find that paraspeckles are transcriptionally inactive but contain polymerase II, which remains stably associated upon transcriptional inhibition, when paraspeckles reorganize around nucleoli in the form of caps.
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Schneider, Jana, Bianca Dauber, Krister Melén, Ilkka Julkunen, and Thorsten Wolff. "Analysis of Influenza B Virus NS1 Protein Trafficking Reveals a Novel Interaction with Nuclear Speckle Domains." Journal of Virology 83, no. 2 (November 5, 2008): 701–11. http://dx.doi.org/10.1128/jvi.01858-08.
Full textAbstract:
ABSTRACT Many proteins that function in the transcription, maturation, and export of metazoan mRNAs are concentrated in nuclear speckle domains, indicating that the compartment is important for gene expression. Here, we show that the NS1 protein of influenza B virus (B/NS1) accumulates in nuclear speckles and causes rounding and morphological changes of the domains, indicating a disturbance in their normal functions. This property was located within the N-terminal 90 amino acids of the B/NS1 protein and was shown to be independent of any other viral gene product. Within this protein domain, we identified a monopartite importin α binding nuclear localization signal. Reverse-genetic analysis of this motif indicated that nuclear import and speckle association of the B/NS1 protein are required for the full replication capacity of the virus. In the late phase of virus infection, the B/NS1 protein relocated to the cytoplasm, which occurred in a CRM1-independent manner. The interaction of the B/NS1 protein with nuclear speckles may reflect a recruitment function to promote viral-gene expression. To our knowledge, this is the first functional description of a speckle-associated protein that is encoded by a negative-strand RNA virus.
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Shakyawar, Dhruv Kumar, Bhattiprolu Muralikrishna, and Vegesna Radha. "C3G dynamically associates with nuclear speckles and regulates mRNA splicing." Molecular Biology of the Cell 29, no. 9 (May 2018): 1111–24. http://dx.doi.org/10.1091/mbc.e17-07-0442.
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C3G (Crk SH3 domain binding guanine nucleotide releasing factor) (Rap guanine nucleotide exchange factor 1), essential for mammalian embryonic development, is ubiquitously expressed and undergoes regulated nucleocytoplasmic exchange. Here we show that C3G localizes to SC35-positive nuclear speckles and regulates splicing activity. Reversible association of C3G with speckles was seen on inhibition of transcription and splicing. C3G shows partial colocalization with SC35 and is recruited to a chromatin and RNase-sensitive fraction of speckles. Its presence in speckles is dependent on intact cellular actin cytoskeleton and is lost on expression of the kinase Clk1. Rap1, a substrate of C3G, is also present in nuclear speckles, and inactivation of Rap signaling by expression of GFP-Rap1GAP alters speckle morphology and number. Enhanced association of C3G with speckles is seen on glycogen synthase kinase 3 beta inhibition or differentiation of C2C12 cells to myotubes. CRISPR/Cas9-mediated knockdown of C3G resulted in altered splicing activity of an artificial gene as well as endogenous CD44. C3G knockout clones of C2C12 as well as MDA-MB-231 cells showed reduced protein levels of several splicing factors compared with control cells. Our results identify C3G and Rap1 as novel components of nuclear speckles and a role for C3G in regulating cellular RNA splicing activity.
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Gama-Carvalho, Margarida, Randy D. Krauss, Lijian Chiang, Juan Valcárcel, Michael R. Green, and Maria Carmo-Fonseca. "Targeting of U2AF65 to Sites of Active Splicing in the Nucleus." Journal of Cell Biology 137, no. 5 (June 2, 1997): 975–87. http://dx.doi.org/10.1083/jcb.137.5.975.
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U2AF65 is an essential splicing factor that promotes binding of U2 small nuclear (sn)RNP at the pre-mRNA branchpoint. Here we describe a novel monoclonal antibody that reacts specifically with U2AF65. Using this antibody, we show that U2AF65 is diffusely distributed in the nucleoplasm with additional concentration in nuclear speckles, which represent subnuclear compartments enriched in splicing snRNPs and other splicing factors. Furthermore, transient expression assays using epitope-tagged deletion mutants of U2AF65 indicate that targeting of the protein to nuclear speckles is not affected by removing either the RNA binding domain, the RS domain, or the region required for interaction with U2AF35. The association of U2AF65 with speckles persists during mitosis, when transcription and splicing are downregulated. Moreover, U2AF65 is localized to nuclear speckles in early G1 cells that were treated with transcription inhibitors during mitosis, suggesting that the localization of U2AF65 in speckles is independent of the presence of pre-mRNA in the nucleus, which is consistent with the idea that speckles represent storage sites for inactive splicing factors. After adenovirus infection, U2AF65 redistributes from the speckles and is prefferentially detected at sites of viral transcription. By combining adenoviral infection with transient expression of deletion mutants, we show a specific requirement of the RS domain for recruitment of U2AF65 to sites of active splicing in the nucleus. This suggests that interactions involving the RS region of U2AF65 may play an important role in targeting this protein to spliceosomes in vivo.
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Cáceres, Javier F., Tom Misteli, Gavin R. Screaton, David L. Spector, and Adrian R. Krainer. "Role of the Modular Domains of SR Proteins in Subnuclear Localization and Alternative Splicing Specificity." Journal of Cell Biology 138, no. 2 (July 28, 1997): 225–38. http://dx.doi.org/10.1083/jcb.138.2.225.
Full textAbstract:
SR proteins are required for constitutive pre-mRNA splicing and also regulate alternative splice site selection in a concentration-dependent manner. They have a modular structure that consists of one or two RNA-recognition motifs (RRMs) and a COOH-terminal arginine/serine-rich domain (RS domain). We have analyzed the role of the individual domains of these closely related proteins in cellular distribution, subnuclear localization, and regulation of alternative splicing in vivo. We observed striking differences in the localization signals present in several human SR proteins. In contrast to earlier studies of RS domains in the Drosophila suppressor-of-white-apricot (SWAP) and Transformer (Tra) alternative splicing factors, we found that the RS domain of SF2/ASF is neither necessary nor sufficient for targeting to the nuclear speckles. Although this RS domain is a nuclear localization signal, subnuclear targeting to the speckles requires at least two of the three constituent domains of SF2/ASF, which contain additive and redundant signals. In contrast, in two SR proteins that have a single RRM (SC35 and SRp20), the RS domain is both necessary and sufficient as a targeting signal to the speckles. We also show that RRM2 of SF2/ASF plays an important role in alternative splicing specificity: deletion of this domain results in a protein that, although active in alternative splicing, has altered specificity in 5′ splice site selection. These results demonstrate the modularity of SR proteins and the importance of individual domains for their cellular localization and alternative splicing function in vivo.
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Prasanth, Kannanganattu V., Matthew Camiolo, Grace Chan, Vidisha Tripathi, Laurence Denis, Tetsuya Nakamura, Michael R. Hübner, and David L. Spector. "Nuclear Organization and Dynamics of 7SK RNA in Regulating Gene Expression." Molecular Biology of the Cell 21, no. 23 (December 2010): 4184–96. http://dx.doi.org/10.1091/mbc.e10-02-0105.
Full textAbstract:
Noncoding RNAs play important roles in various aspects of gene regulation. We have identified 7SK RNA to be enriched in nuclear speckles or interchromatin granule clusters (IGCs), a subnuclear domain enriched in pre-mRNA processing factors. 7SK RNA, in association with HEXIM 1 and 2, is involved in the inhibition of transcriptional elongation by RNA polymerase II. Inhibition occurs via sequestration of the active P-TEFb kinase complex (CDK 9 and Cyclin T1/T2a/b or K) that is involved in phosphorylating the C-terminal domain of RNA polymerase II. Our results demonstrate that knock-down of 7SK RNA, by specific antisense oligonucleotides, results in the mislocalization of nuclear speckle constituents in a transcription-dependent manner, and the transcriptional up-regulation of a RNA polymerase II transcribed reporter gene locus. Furthermore, 7SK RNA transiently associates with a stably integrated reporter gene locus upon transcriptional down-regulation and its presence correlates with the efficient displacement of P-TEFb constituents from the locus. Our results suggest that 7SK RNA plays a role in modulating the available level of P-TEFb upon transcriptional down-regulation by sequestering its constituents in nuclear speckles.
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Burgute, Bhagyashri D., Vivek S. Peche, Anna-Lena Steckelberg, Gernot Glöckner, Berthold Gaßen, Niels H. Gehring, and Angelika A. Noegel. "NKAP is a novel RS-related protein that interacts with RNA and RNA binding proteins." Nucleic Acids Research 42, no. 5 (December 17, 2013): 3177–93. http://dx.doi.org/10.1093/nar/gkt1311.
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Abstract NKAP is a highly conserved protein with roles in transcriptional repression, T-cell development, maturation and acquisition of functional competency and maintenance and survival of adult hematopoietic stem cells. Here we report the novel role of NKAP in splicing. With NKAP-specific antibodies we found that NKAP localizes to nuclear speckles. NKAP has an RS motif at the N-terminus followed by a highly basic domain and a DUF 926 domain at the C-terminal region. Deletion analysis showed that the basic domain is important for speckle localization. In pull-down experiments, we identified RNA-binding proteins, RNA helicases and splicing factors as interaction partners of NKAP, among them FUS/TLS. The FUS/TLS–NKAP interaction takes place through the RS domain of NKAP and the RGG1 and RGG3 domains of FUS/TLS. We analyzed the ability of NKAP to interact with RNA using in vitro splicing assays and found that NKAP bound both spliced messenger RNA (mRNA) and unspliced pre-mRNA. Genome-wide analysis using crosslinking and immunoprecipitation-seq revealed NKAP association with U1, U4 and U5 small nuclear RNA, and we also demonstrated that knockdown of NKAP led to an increase in pre-mRNA percentage. Our results reveal NKAP as nuclear speckle protein with roles in RNA splicing and processing.
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Misteli, Tom, Javier F. Cáceres, Jade Q. Clement, Adrian R. Krainer, Miles F. Wilkinson, and David L. Spector. "Serine Phosphorylation of SR Proteins Is Required for Their Recruitment to Sites of Transcription In Vivo." Journal of Cell Biology 143, no. 2 (October 19, 1998): 297–307. http://dx.doi.org/10.1083/jcb.143.2.297.
Full textAbstract:
Expression of most RNA polymerase II transcripts requires the coordinated execution of transcription, splicing, and 3′ processing. We have previously shown that upon transcriptional activation of a gene in vivo, pre-mRNA splicing factors are recruited from nuclear speckles, in which they are concentrated, to sites of transcription (Misteli, T., J.F. Cáceres, and D.L. Spector. 1997. Nature. 387:523–527). This recruitment process appears to spatially coordinate transcription and pre-mRNA splicing within the cell nucleus. Here we have investigated the molecular basis for recruitment by analyzing the recruitment properties of mutant splicing factors. We show that multiple protein domains are required for efficient recruitment of SR proteins from nuclear speckles to nascent RNA. The two types of modular domains found in the splicing factor SF2/ ASF exert distinct functions in this process. In living cells, the RS domain functions in the dissociation of the protein from speckles, and phosphorylation of serine residues in the RS domain is a prerequisite for this event. The RNA binding domains play a role in the association of splicing factors with the target RNA. These observations identify a novel in vivo role for the RS domain of SR proteins and suggest a model in which protein phosphorylation is instrumental for the recruitment of these proteins to active sites of transcription in vivo.
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Jagiello, I., A. Van Eynde, V. Vulsteke, M. Beullens, A. Boudrez, S. Keppens, W. Stalmans, and M. Bollen. "Nuclear and subnuclear targeting sequences of the protein phosphatase-1 regulator NIPP1." Journal of Cell Science 113, no. 21 (November 1, 2000): 3761–68. http://dx.doi.org/10.1242/jcs.113.21.3761.
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NIPP1 is a nuclear subunit of protein phosphatase-1 (PP1) that colocalizes with pre-mRNA splicing factors in speckles. We report here that the nuclear and subnuclear targeting of NIPP1, when expressed in HeLa cells or COS-1 cells as a fusion protein with the enhanced-green-fluorescent protein (EGFP), are mediated by distinct sequences. While NIPP1-EGFP can cross the nuclear membrane passively, the active transport to the nucleus is mediated by two independent nuclear localization signals in the central domain of NIPP1, which partially overlap with binding site(s) for PP1. Furthermore, the concentration of NIPP1-EGFP in the nuclear speckles requires the ‘ForkHead-Associated’ domain in the N terminus. This domain is also required for the nuclear retention of NIPP1 when active transport is blocked. Our data imply that the nuclear and subnuclear targeting of NIPP1 are controlled independently.
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Miyagi, Tamami, Rio Yamazaki, Koji Ueda, Satoshi Narumi, Yuhei Hayamizu, Hiroshi Uji-i, Masahiko Kuroda, and Kohsuke Kanekura. "The Patterning and Proportion of Charged Residues in the Arginine-Rich Mixed-Charge Domain Determine the Membrane-Less Organelle Targeted by the Protein." International Journal of Molecular Sciences 23, no. 14 (July 11, 2022): 7658. http://dx.doi.org/10.3390/ijms23147658.
Full textAbstract:
Membrane-less organelles (MLOs) are formed by biomolecular liquid–liquid phase separation (LLPS). Proteins with charged low-complexity domains (LCDs) are prone to phase separation and localize to MLOs, but the mechanism underlying the distributions of such proteins to specific MLOs remains poorly understood. Recently, proteins with Arg-enriched mixed-charge domains (R-MCDs), primarily composed of R and Asp (D), were found to accumulate in nuclear speckles via LLPS. However, the process by which R-MCDs selectively incorporate into nuclear speckles is unknown. Here, we demonstrate that the patterning of charged amino acids and net charge determines the targeting of specific MLOs, including nuclear speckles and the nucleolus, by proteins. The redistribution of R and D residues from an alternately sequenced pattern to uneven blocky sequences caused a shift in R-MCD distribution from nuclear speckles to the nucleolus. In addition, the incorporation of basic residues in the R-MCDs promoted their localization to the MLOs and their apparent accumulation in the nucleolus. The R-MCD peptide with alternating amino acids did not undergo LLPS, whereas the blocky R-MCD peptide underwent LLPS with affinity to RNA, acidic poly-Glu, and the acidic nucleolar protein nucleophosmin, suggesting that the clustering of R residues helps avoid their neutralization by D residues and eventually induces R-MCD migration to the nucleolus. Therefore, the distribution of proteins to nuclear speckles requires the proximal positioning of D and R for the mutual neutralization of their charges.
Dissertations / Theses on the topic "Nuclear speckles domain"
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Mlaza, Mihlali. "Investigation of the role of the ubiquitin-like DWNN domain in targeting Retinoblastoma Binding Protein 6 to nuclear speckles." University of the Western Cape, 2018. http://hdl.handle.net/11394/6200.
Full textAbstract:
Retinoblastoma Binding Protein 6 (RBBP6) is a 200 KDa protein shown to play a role in 3'-
polyadenylation of mRNA transcripts, as well as to function as an E3 ligase catalysing
ubiquitination of cancer-associated proteins. RBBP6 has been previously reported to localise to
nuclear speckles, which are thought to play a role in mRNA splicing, presumably as a result of
its RS domain, which is known to target mRNA splicing factors to nuclear speckles. However
recent studies in our laboratory have shown that isoform 3 of RBBP6, consisting mainly of the
DWNN domain, also localises to speckles in resting cells, but more strongly in cells subjected to
various stresses, suggesting that the DWNN domain may be the speckle-targeting domain.Magister Scientiae - MSc (Biotechnology)
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GRILLO, BARBARA. "PARTNERS, TARGETS AND MODULATORS OF LSD1 IN STRESS-RESPONSE REGULATION." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/612975.
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In mammals, different forms of stress, including psychosocial stress, can affect various aspects of human health, promoting mood and anxiety disorders. However, very little is known about the mechanisms underlying the brain physiology of stress response, hindering the development of new therapeutic strategies. We uncover a role for the transcriptional corepressor Lysine Specific Demethylase-1 (LSD1) and its dominant negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In the mouse hippocampus, LSD1 and neuroLSD1 interacting with the transcription factor Serum Response Factor (SRF) and SRFΔ5 participate as molecular transducers of stress stimuli. Likewise LSD1, also SRF is modulated by an alternative splicing isoform without transactivation domain, SRFΔ5. Psychosocial stress acutely reduces the expression of neuroLSD1 through a splicing-based modulation that results in an increase in the amount of LSD1, while the relative ratio between SRF and SRFΔ5 is sensitive both to ASDS and CSDS. Furthermore, SRFΔ5 shows SUS-restricted downregulation that might contribute to shaping psychosocial stress vulnerability, through interfering with homeostatic mechanisms underlying stress resiliency. All these data suggest the involvement of the dual LSD1/neuroLSD1 and SRF/SRFΔ5 in the adaptive response to stress.
Alternative splicing is a strategic biological mechanism that allows to create a set of functionally different gene products from a single gene, diversifying gene functions without an increase in the number of genes. neuroLSD1, an activity-dependent splicing isoform that differs from LSD1 for the inclusion of exon 8a, was related to important homeostatic neuronal functions impacting emotional processing. It has recently been published that MALAT1(metastasis associated lung adenocarcinoma transcript 1), a long non-coding RNA, has a crucial role in the alternative splicing mechanism of some genes through the regulation of the splicing factor SRSF1, belonging to the SR protein family. In particular MALAT1 is mainly localized at the level of the nuclear speckles, where it seems to regulate the alternative splicing through the retention of SRSF1 in these nuclear domains and the modulation of their phosphorylation state through an unknown mechanism. We already published that alternative splicing involving LSD1 is positively regulated in trans by two splicing factors NOVA1 and nSR100. In particular, nSR100 is a splicing factor belonging to the SR protein family, as SRSF1, and regulates tissue-specific alternative splicing in a manner dependent on its concentration and its phosphorylation status.
We propose MALAT1 as a negative modulator of the neurospecific splicing of LSD1, in particular following ASDS the increased levels of MALAT1 lead to the sequestration of nSR100 at the level of nuclear speckles, making clear the mechanism behind the decrease of the dominant negative neuroLSD1 expression levels following stress
We found that following a chronic psychosocial stress the expression levels of MALAT1 seem to be positively regulated only in resilient individuals who manage to maintain physiological expression levels of IEG in the hippocampus. Our hypothesis is that only resilient subjects are still able to modulate maladaptive stress-related transcription, thanks to the increased levels of MALAT1, bringing the system back to basal physiological conditions through the negative regulation of neuroLSD1 formation. All this suggests that MALAT1 could be considered a possible hallmark of resilience.
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Domínguez, Solà David. "Mecanismes de regulació en l'activitat biològica del factor de transcripció Snail." Doctoral thesis, Universitat Pompeu Fabra, 2003. http://hdl.handle.net/10803/7065.
Full textAbstract:
Els factors de transcripció de la família Snail són fonamentals en la "transició epiteli-mesènquima", procés morfogènic essencial en el desenvolupament embrionari i en els fenòmens metastàsics tumorals.En els mamífers l'activitat d'Snail és modulada per dos mecanismes. (i) En el promotor humà es troben regions definides de resposta a factors repressors, predominants en les cèl·lules epitelials, i elements diferenciats de resposta a inductors de la "transició epiteli-mesènquima". (ii) L'activitat d'Snail és condicionada també per la seva localització subcel·lular, modulada per mecanismes no transcripcionals: la fosforilació d'Snail determina si és o no exclós del nucli. Al citosol no pot actuar com a repressor transcripcional però pot interaccionar amb la xarxa microtubular, que estabilitza i en condiciona el dinamisme. Això coincideix amb l'activació de la GTPasa RhoA i la reorientació dels filaments de vimentina, fets associats a l'adquisició de capacitat migratòria. L'efecte com a repressor transcripcional i la modulació del dinamisme microtubular són possiblement esdeveniments coordinats necessaris per al rol biològic d'Snail en mamífers.
Snail family of transcription factors is fundamental to the "epithelial-mesenchymal transition", morphogenic process essential to embryonic development and metastatic phenomena in tumors.
Snail's activity is modulated in two ways in mammals. (i) The human promoter harbors definite regions that respond to repressor factors, which prevail in epithelial cells; and differentiated elements that respond to known inducers of the "epithelial-mesenchymal transition". (ii) Snail's activity is also conditioned by its subcellular localization, mechanism not dependent on its transcriptional control: Snail phosphorylation determines whether Snail is excluded or not from the nucleus. When in the cytosol, Snail is unable to act as a transcriptional repressor, but however binds to the microtubular meshwork, which becomes stabilized and whose dynamism is conditioned as a result. This fact coincides with the activation of the RhoA GTPase and reorientation of vimentin filaments, both phenomena being related to the acquisition of cell motility. The transcriptional repressor and the microtubule dynamics effects are probably two coordinated events necessary to Snail's biological role in mammals.