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Hoffmann, Tobias y Juan Valcárcel. "Splicing Calls Back". Cell 179, n.º 7 (diciembre de 2019): 1446–47. http://dx.doi.org/10.1016/j.cell.2019.11.028.
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Wang, Jun y Liangjiang Wang. "Deep learning of the back-splicing code for circular RNA formation". Bioinformatics 35, n.º 24 (11 de mayo de 2019): 5235–42. http://dx.doi.org/10.1093/bioinformatics/btz382.
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Abstract Motivation Circular RNAs (circRNAs) are a new class of endogenous RNAs in animals and plants. During pre-RNA splicing, the 5′ and 3′ termini of exon(s) can be covalently ligated to form circRNAs through back-splicing (head-to-tail splicing). CircRNAs can be conserved across species, show tissue- and developmental stage-specific expression patterns, and may be associated with human disease. However, the mechanism of circRNA formation is still unclear although some sequence features have been shown to affect back-splicing. Results In this study, by applying the state-of-art machine learning techniques, we have developed the first deep learning model, DeepCirCode, to predict back-splicing for human circRNA formation. DeepCirCode utilizes a convolutional neural network (CNN) with nucleotide sequence as the input, and shows superior performance over conventional machine learning algorithms such as support vector machine and random forest. Relevant features learnt by DeepCirCode are represented as sequence motifs, some of which match human known motifs involved in RNA splicing, transcription or translation. Analysis of these motifs shows that their distribution in RNA sequences can be important for back-splicing. Moreover, some of the human motifs appear to be conserved in mouse and fruit fly. The findings provide new insight into the back-splicing code for circRNA formation. Availability and implementation All the datasets and source code for model construction are available at https://github.com/BioDataLearning/DeepCirCode. Supplementary information Supplementary data are available at Bioinformatics online.
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Zhang, Xiao-Ou, Rui Dong, Yang Zhang, Jia-Lin Zhang, Zheng Luo, Jun Zhang, Ling-Ling Chen y Li Yang. "Diverse alternative back-splicing and alternative splicing landscape of circular RNAs". Genome Research 26, n.º 9 (30 de junio de 2016): 1277–87. http://dx.doi.org/10.1101/gr.202895.115.
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Zhang, Peng, Xiao-Ou Zhang, Tingting Jiang, Lingling Cai, Xiao Huang, Qi Liu, Dan Li et al. "Comprehensive identification of alternative back-splicing in human tissue transcriptomes". Nucleic Acids Research 48, n.º 4 (24 de enero de 2020): 1779–89. http://dx.doi.org/10.1093/nar/gkaa005.
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Abstract Circular RNAs (circRNAs) are covalently closed RNAs derived from back-splicing of genes across eukaryotes. Through alternative back-splicing (ABS), a single gene produces multiple circRNAs sharing the same back-splice site. Although many ABS events have recently been discovered, to what extent ABS involves in circRNA biogenesis and how it is regulated in different human tissues still remain elusive. Here, we reported an in-depth analysis of ABS events in 90 human tissue transcriptomes. We observed that ABS occurred for about 84% circRNAs. Interestingly, alternative 5′ back-splicing occurs more prevalently than alternative 3′ back-splicing, and both of them are tissue-specific, especially enriched in brain tissues. In addition, the patterns of ABS events in different brain regions are similar to each other and are more complex than the patterns in non-brain tissues. Finally, the intron length and abundance of Alu elements positively correlated with ABS event complexity, and the predominant circRNAs had longer flanking introns and more Alu elements than other circRNAs in the same ABS event. Together, our results represent a resource for circRNA research—we expanded the repertoire of ABS events of circRNAs in human tissue transcriptomes and provided insights into the complexity of circRNA biogenesis, expression, and regulation.
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Zlotorynski, Eytan. "Intron definition, exon definition and back-splicing revisited". Nature Reviews Molecular Cell Biology 20, n.º 11 (23 de septiembre de 2019): 661. http://dx.doi.org/10.1038/s41580-019-0178-3.
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Zhang, Ke, Guijun Shang, Abhilash Padavannil, Juan Wang, Ramanavelan Sakthivel, Xiang Chen, Min Kim et al. "Structural–functional interactions of NS1-BP protein with the splicing and mRNA export machineries for viral and host gene expression". Proceedings of the National Academy of Sciences 115, n.º 52 (11 de diciembre de 2018): E12218—E12227. http://dx.doi.org/10.1073/pnas.1818012115.
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The influenza virulence factor NS1 protein interacts with the cellular NS1-BP protein to promote splicing and nuclear export of the viral M mRNAs. The viral M1 mRNA encodes the M1 matrix protein and is alternatively spliced into the M2 mRNA, which is translated into the M2 ion channel. These proteins have key functions in viral trafficking and budding. To uncover the NS1-BP structural and functional activities in splicing and nuclear export, we performed proteomics analysis of nuclear NS1-BP binding partners and showed its interaction with constituents of the splicing and mRNA export machineries. NS1-BP BTB domains form dimers in the crystal. Full-length NS1-BP is a dimer in solution and forms at least a dimer in cells. Mutations suggest that dimerization is important for splicing. The central BACK domain of NS1-BP interacts directly with splicing factors such as hnRNP K and PTBP1 and with the viral NS1 protein. The BACK domain is also the site for interactions with mRNA export factor Aly/REF and is required for viral M mRNA nuclear export. The crystal structure of the C-terminal Kelch domain shows that it forms a β-propeller fold, which is required for the splicing function of NS1-BP. This domain interacts with the polymerase II C-terminal domain and SART1, which are involved in recruitment of splicing factors and spliceosome assembly, respectively. NS1-BP functions are not only critical for processing a subset of viral mRNAs but also impact levels and nuclear export of a subset of cellular mRNAs encoding factors involved in metastasis and immunity.
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Pitolli, Consuelo, Alberto Marini, Claudio Sette y Vittoria Pagliarini. "Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer". International Journal of Molecular Sciences 23, n.º 5 (4 de marzo de 2022): 2811. http://dx.doi.org/10.3390/ijms23052811.
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The advance of experimental and computational techniques has allowed us to highlight the existence of numerous different mechanisms of RNA maturation, which have been so far unknown. Besides canonical splicing, consisting of the removal of introns from pre-mRNA molecules, non-canonical splicing events may occur to further increase the regulatory and coding potential of the human genome. Among these, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and trans-splicing processes, respectively, all contribute to expanding the repertoire of RNA transcripts with newly acquired regulatory functions. Interestingly, these non-canonical splicing events seem to occur more frequently in the central nervous system, affecting neuronal development and differentiation programs with important implications on brain physiology. Coherently, dysregulation of non-canonical RNA processing events is associated with brain disorders, including brain tumours. Herein, we summarize the current knowledge on molecular and regulatory mechanisms underlying canonical and non-canonical splicing events with particular emphasis on cis-acting elements and trans-acting factors that all together orchestrate splicing catalysis reactions and decisions. Lastly, we review the impact of non-canonical splicing on brain physiology and pathology and how unconventional splicing mechanisms may be targeted or exploited for novel therapeutic strategies in cancer.
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Hasimbegovic, Ena, Victor Schweiger, Nina Kastner, Andreas Spannbauer, Denise Traxler, Dominika Lukovic, Mariann Gyöngyösi y Julia Mester-Tonczar. "Alternative Splicing in Cardiovascular Disease—A Survey of Recent Findings". Genes 12, n.º 9 (21 de septiembre de 2021): 1457. http://dx.doi.org/10.3390/genes12091457.
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Alternative splicing, a driver of posttranscriptional variance, differs from canonical splicing by arranging the introns and exons of an immature pre-mRNA transcript in a multitude of different ways. Although alternative splicing was discovered almost half a century ago, estimates of the proportion of genes that undergo alternative splicing have risen drastically over the last two decades. Deep sequencing methods and novel bioinformatic algorithms have led to new insights into the prevalence of spliced variants, tissue-specific splicing patterns and the significance of alternative splicing in development and disease. Thus far, the role of alternative splicing has been uncovered in areas ranging from heart development, the response to myocardial infarction to cardiac structural disease. Circular RNAs, a product of alternative back-splicing, were initially discovered in 1976, but landmark publications have only recently identified their regulatory role, tissue-specific expression, and transcriptomic abundance, spurring a renewed interest in the topic. The aim of this review is to provide a brief insight into some of the available findings on the role of alternative splicing in cardiovascular disease, with a focus on atherosclerosis, myocardial infarction, heart failure, dilated cardiomyopathy and circular RNAs in myocardial infarction.
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Tijsen, Anke J., Lucía Cócera Ortega, Yolan J. Reckman, Xiaolei Zhang, Ingeborg van der Made, Simona Aufiero, Jiuru Li et al. "Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10 Splicing". Circulation 143, n.º 15 (13 de abril de 2021): 1502–12. http://dx.doi.org/10.1161/circulationaha.120.050455.
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Background: TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the TTN transcript are the most frequent cause of hereditary heart failure. We showed before that TTN produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20. Methods: We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes. Results: Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as MEF2A and CASQ2 . Strikingly, loss of cTTN1 also caused abnormal splicing of TTN itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20. Conclusions: We demonstrate that circRNAs formed from the TTN transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the TTN transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.
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Lezzhov, Alexander A., Anastasia K. Atabekova, Denis A. Chergintsev, Ekaterina A. Lazareva, Andrey G. Solovyev y Sergey Y. Morozov. "Viroids and Retrozymes: Plant Circular RNAs Capable of Autonomous Replication". Plants 14, n.º 1 (27 de diciembre de 2024): 61. https://doi.org/10.3390/plants14010061.
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Among the long non-coding RNAs that are currently recognized as important regulatory molecules influencing a plethora of processes in eukaryotic cells, circular RNAs (circRNAs) represent a distinct class of RNAs that are predominantly produced by back-splicing of pre-mRNA. The most studied regulatory mechanisms involving circRNAs are acting as miRNA sponges, forming R-loops with genomic DNA, and encoding functional proteins. In addition to circRNAs generated by back-splicing, two types of circRNAs capable of autonomous RNA-RNA replication and systemic transport have been described in plants: viroids, which are infectious RNAs that cause a number of plant diseases, and retrozymes, which are transcripts of retrotransposon genomic loci that are capable of circularization due to ribozymes. Based on a number of common features, viroids and retrozymes are considered to be evolutionarily related. Here, we provide an overview of the biogenesis mechanisms and regulatory functions of non-replicating circRNAs produced by back-splicing and further discuss in detail the currently available data on viroids and retrozymes, focusing on their structural features, replication mechanisms, interaction with cellular components, and transport in plants. In addition, biotechnological approaches involving replication-capable plant circRNAs are discussed, as well as their potential applications in research and agriculture.
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Vincent, Kevin, Qiang Wang, Steven Jay, Kathryn Hobbs y Brian C. Rymond. "Genetic Interactions WithCLF1Identify Additional Pre-mRNA Splicing Factors and a Link Between Activators of Yeast Vesicular Transport and Splicing". Genetics 164, n.º 3 (1 de julio de 2003): 895–907. http://dx.doi.org/10.1093/genetics/164.3.895.
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AbstractClf1 is a conserved spliceosome assembly factor composed predominately of TPR repeats. Here we show that the TPR elements are not functionally equivalent, with the amino terminus of Clf1 being especially sensitive to change. Deletion and add-back experiments reveal that the splicing defect associated with TPR removal results from the loss of TPR-specific sequence information. Twelve mutants were found that show synthetic growth defects when combined with an allele that lacks TPR2 (i.e., clf1Δ2). The identified genes encode the Mud2, Ntc20, Prp16, Prp17, Prp19, Prp22, and Syf2 splicing factors and four proteins without established contribution to splicing (Bud13, Cet1, Cwc2, and Rds3). Each synthetic lethal with clf1Δ2 (slc) mutant is splicing defective in a wild-type CLF1 background. In addition to the splicing factors, SSD1, BTS1, and BET4 were identified as dosage suppressors of clf1Δ2 or selected slc mutants. These results support Clf1 function through multiple stages of the spliceosome cycle, identify additional genes that promote cellular mRNA maturation, and reveal a link between Rab/Ras GTPase activation and the process of pre-mRNA splicing.
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Li, Qin, Hongyan Lai, Yuchen Li, Bing Chen, Siyuan Chen, Yan Li, Zhaohui Huang et al. "RJunBase: a database of RNA splice junctions in human normal and cancerous tissues". Nucleic Acids Research 49, n.º D1 (12 de noviembre de 2020): D201—D211. http://dx.doi.org/10.1093/nar/gkaa1056.
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Abstract Splicing is an essential step of RNA processing for multi-exon genes, in which introns are removed from a precursor RNA, thereby producing mature RNAs containing splice junctions. Here, we develope the RJunBase (www.RJunBase.org), a web-accessible database of three types of RNA splice junctions (linear, back-splice, and fusion junctions) that are derived from RNA-seq data of non-cancerous and cancerous tissues. The RJunBase aims to integrate and characterize all RNA splice junctions of both healthy or pathological human cells and tissues. This new database facilitates the visualization of the gene-level splicing pattern and the junction-level expression profile, as well as the demonstration of unannotated and tumor-specific junctions. The first release of RJunBase contains 682 017 linear junctions, 225 949 back-splice junctions and 34 733 fusion junctions across 18 084 non-cancerous and 11 540 cancerous samples. RJunBase can aid researchers in discovering new splicing-associated targets and provide insights into the identification and assessment of potential neoepitopes for cancer treatment.
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Yildirim, Adem, Sina Mozaffari-Jovin, Ann-Kathrin Wallisch, Jessica Schäfer, Sebastian E. J. Ludwig, Henning Urlaub, Reinhard Lührmann y Uwe Wolfrum. "SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes". Nucleic Acids Research 49, n.º 10 (22 de mayo de 2021): 5845–66. http://dx.doi.org/10.1093/nar/gkab386.
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Abstract Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal links between splicing machinery components and the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome—the most common cause of deaf-blindness. Previously, SANS was shown to function only in the cytosol and primary cilia. Here, we have uncovered molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome in the nucleus. We show that SANS is found in Cajal bodies and nuclear speckles, where it interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome assembly and may also participate in snRNP recycling back to Cajal bodies. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and human Usher syndrome. Thus, we provide the first evidence that splicing dysregulation may participate in the pathophysiology of Usher syndrome.
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Shang, Jin, Xin Fan, Lei Shangguan, Huan Liu y Yue Zhou. "Global Gene Expression Profiling and Alternative Splicing Events during the Chondrogenic Differentiation of Human Cartilage Endplate-Derived Stem Cells". BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/604972.
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Low back pain (LBP) is a very prevalent disease and degenerative disc diseases (DDDs) usually account for the LBP. However, the pathogenesis of DDDs is complicated and difficult to elucidate. Alternative splicing is a sophisticated regulatory process which greatly increases cellular complexity and phenotypic diversity of eukaryotic organisms. In addition, the cartilage endplate-derived stem cells have been discovered and identified by our research group. In this paper, we continue to investigate gene expression profiling and alternative splicing events during chondrogenic differentiation of cartilage endplate-derived stem cells. We adopted Affymetrix Human Transcriptome Array 2.0 (HTA 2.0) to compare the transcriptional and splicing changes between the control and differentiated samples. RT-PCR and quantitative PCR are used to validate the microarray results. The GO and KEGG pathway analysis was also performed. After bioinformatics analysis of the data, we detected 1953 differentially expressed genes. In terms of alternative splicing, the Splicing Index algorithm was used to select alternatively spliced genes. We detected 4411 alternatively spliced genes. GO and KEGG pathway analysis also revealed several functionally involved biological processes and signaling pathways. To our knowledge, this is the first study to investigate the alternative splicing mechanisms in chondrogenic differentiation of stem cells on a genome-wide scale.
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Huang, Ying, Haofei Ji, Jiani Dong, Xueying Wang, Zhilin He, Zeneng Cheng y Qubo Zhu. "CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma". Cancers 15, n.º 16 (11 de agosto de 2023): 4057. http://dx.doi.org/10.3390/cancers15164057.
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CircRNAs are crucial in tumorigenesis and metastasis, and are comprehensively downregulated in hepatocellular carcinoma (HCC). Previous studies demonstrated that the back-splicing of circRNAs was closely related to 3′-end splicing. As a core executor of 3′-end cleavage, we hypothesized that CPSF3 modulated circRNA circularization. Clinical data were analyzed to establish the prognostic correlations. Cytological experiments were performed to determine the role of CPSF3 in HCC. A fluorescent reporter was employed to explore the back-splicing mechanism. The circRNAs regulated by CPSF3 were screened by RNA-seq and validated by PCR, and changes in downstream pathways were explored by molecular experiments. Finally, the safety and efficacy of the CPSF3 inhibitor JTE-607 were verified both in vitro and in vivo. The results showed that CPSF3 was highly expressed in HCC cells, promoting their proliferation and migration, and that a high CPSF3 level was predictive of a poor prognosis. A mechanistic study revealed that CPSF3 enhanced RNA cleavage, thereby reducing circRNAs, and increasing linear mRNAs. Furthermore, inhibition of CPSF3 by JET-607 suppressed the proliferation of HCC cells. Our findings indicate that the increase of CPSF3 in HCC promotes the shift of pre-mRNA from circRNA to linear mRNA, leading to uncontrolled cell proliferation. JTE-607 exerted a therapeutic effect on HCC by blocking CPSF3.
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Bilodeau, Patricia S., Jeffrey K. Domsic, Akila Mayeda, Adrian R. Krainer y C. Martin Stoltzfus. "RNA Splicing at Human Immunodeficiency Virus Type 1 3′ Splice Site A2 Is Regulated by Binding of hnRNP A/B Proteins to an Exonic Splicing Silencer Element". Journal of Virology 75, n.º 18 (15 de septiembre de 2001): 8487–97. http://dx.doi.org/10.1128/jvi.75.18.8487-8497.2001.
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ABSTRACT The synthesis of human immunodeficiency virus type 1 (HIV-1) mRNAs is a complex process by which more than 30 different mRNA species are produced by alternative splicing of a single primary RNA transcript. HIV-1 splice sites are used with significantly different efficiencies, resulting in different levels of mRNA species in infected cells. Splicing of Tat mRNA, which is present at relatively low levels in infected cells, is repressed by the presence of exonic splicing silencers (ESS) within the two tat coding exons (ESS2 and ESS3). These ESS elements contain the consensus sequence PyUAG. Here we show that the efficiency of splicing at 3′ splice site A2, which is used to generate Vpr mRNA, is also regulated by the presence of an ESS (ESSV), which has sequence homology to ESS2 and ESS3. Mutagenesis of the three PyUAG motifs within ESSV increases splicing at splice site A2, resulting in increased Vpr mRNA levels and reduced skipping of the noncoding exon flanked by A2 and D3. The increase in Vpr mRNA levels and the reduced skipping also occur when splice site D3 is mutated toward the consensus sequence. By in vitro splicing assays, we show that ESSV represses splicing when placed downstream of a heterologous splice site. A1, A1B, A2, and B1 hnRNPs preferentially bind to ESSV RNA compared to ESSV mutant RNA. Each of these proteins, when added back to HeLa cell nuclear extracts depleted of ESSV-binding factors, is able to restore splicing repression. The results suggest that coordinate repression of HIV-1 RNA splicing is mediated by members of the hnRNP A/B protein family.
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Lu, Xin-Hong, Jingshang Zhou, Liuqing Li, Tianmin Zhou, Zhanfeng Cao y Guangcai Yuan. "P‐133: Research of Novel Splicing Technique on Glass‐based Micro LED Display". SID Symposium Digest of Technical Papers 54, n.º 1 (junio de 2023): 1365–68. http://dx.doi.org/10.1002/sdtp.16837.
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With the rapid development of Micro LED display technology, glass‐based splicing solution has been an important project for large‐sized displays. Herein, a novel curvely bending technique was demonstrated, in which the non‐display areas of the Micro LED panel could be folded onto the back surface of the display areas. A curve border as narrow as 150 um was achieved, equal to that of BOE's aforepublicated side wiring technique. In view of the single‐side backplane process adopted, the manufacturing cost was considered to be significantly reduced, which made the bending technique a promising solution to the splicing Micro LED displays.
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Dutta, Aparajita, Kusum Kumari Singh y Ashish Anand. "SpliceViNCI: Visualizing the splicing of non-canonical introns through recurrent neural networks". Journal of Bioinformatics and Computational Biology 19, n.º 04 (4 de junio de 2021): 2150014. http://dx.doi.org/10.1142/s0219720021500141.
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Most of the current computational models for splice junction prediction are based on the identification of canonical splice junctions. However, it is observed that the junctions lacking the consensus dimers GT and AG also undergo splicing. Identification of such splice junctions, called the non-canonical splice junctions, is also essential for a comprehensive understanding of the splicing phenomenon. This work focuses on the identification of non-canonical splice junctions through the application of a bidirectional long short-term memory (BLSTM) network. Furthermore, we apply a back-propagation-based (integrated gradient) and a perturbation-based (occlusion) visualization techniques to extract the non-canonical splicing features learned by the model. The features obtained are validated with the existing knowledge from the literature. Integrated gradient extracts features that comprise contiguous nucleotides, whereas occlusion extracts features that are individual nucleotides distributed across the sequence.
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Li, Xueni, Shiheng Liu, Lingdi Zhang, Aaron Issaian, Ryan C. Hill, Sara Espinosa, Shasha Shi et al. "A unified mechanism for intron and exon definition and back-splicing". Nature 573, n.º 7774 (4 de septiembre de 2019): 375–80. http://dx.doi.org/10.1038/s41586-019-1523-6.
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Guil, Sònia, Renata Gattoni, Montserrat Carrascal, Joaquín Abián, James Stévenin y Montse Bach-Elias. "Roles of hnRNP A1, SR Proteins, and p68 Helicase in c-H-ras Alternative Splicing Regulation". Molecular and Cellular Biology 23, n.º 8 (15 de abril de 2003): 2927–41. http://dx.doi.org/10.1128/mcb.23.8.2927-2941.2003.
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ABSTRACT Human ras genes play central roles in coupling extracellular signals with complex intracellular networks controlling proliferation, differentiation, and apoptosis, among others processes. c-H-ras pre-mRNA can be alternatively processed into two mRNAs due to the inclusion or exclusion of the alternative exon IDX; this renders two proteins, p21H-Ras and p19H-RasIDX, which differ only at the carboxy terminus. Here, we have characterized some of the cis-acting sequences and trans-acting factors regulating IDX splicing. A downstream intronic silencer sequence (rasISS1), acting in concert with IDX, negatively regulates upstream intron splicing. This effect is mediated, at least in part, by the binding of hnRNP A1. Depletion and add-back experiments in nuclear extracts have confirmed hnRNP A1's inhibitory role in IDX splicing. Moreover, the addition of two SR proteins, SC35 and SRp40, can counteract this inhibition by strongly promoting the splicing of the upstream intron both in vivo and in vitro. Further, the RNA-dependent helicase p68 is also associated with both IDX and rasISS1 RNA, and suppression of p68 expression in HeLa cells by RNAi experiments results in a marked increase of IDX inclusion in the endogenous mRNA, suggesting a role for this protein in alternative splicing regulation.
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Humphreys, David T., Nicolas Fossat, Madeleine Demuth, Patrick P. L. Tam y Joshua W. K. Ho. "Ularcirc: visualization and enhanced analysis of circular RNAs via back and canonical forward splicing". Nucleic Acids Research 47, n.º 20 (22 de agosto de 2019): e123-e123. http://dx.doi.org/10.1093/nar/gkz718.
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Abstract Circular RNAs (circRNA) are a unique class of transcripts that can only be identified from sequence alignments spanning discordant junctions, commonly referred to as backsplice junctions (BSJ). Canonical splicing is also linked with circRNA biogenesis either from the parental transcript or internal to the circRNA, and is not fully utilized in circRNA software. Here we present Ularcirc, a software tool that integrates the visualization of both BSJ and forward splicing junctions and provides downstream analysis of selected circRNA candidates. Ularcirc utilizes the output of CIRI, circExplorer, or raw chimeric output of the STAR aligner and assembles BSJ count table to allow multi-sample analysis. We used Ularcirc to identify and characterize circRNA from public and in-house generated data sets and demonstrate how it can be used to (i) discover novel splicing patterns of parental transcripts, (ii) detect internal splicing patterns of circRNA, and (iii) reveal the complexity of BSJ formation. Furthermore, we identify circRNA that have potential open reading frames longer than their linear sequence. Finally, we detected and validated the presence of a novel class of circRNA generated from ApoA4 transcripts whose BSJ derive from multiple non-canonical splicing sites within coding exons. Ularcirc is accessed via https://github.com/VCCRI/Ularcirc.
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Vaishnavi, D., T. S. Subashini, G. N. Balaji y D. Mahalakshmi. "LBP and GLCM Based Image Forgery Recognition". International Journal of Engineering & Technology 7, n.º 4.6 (25 de septiembre de 2018): 217. http://dx.doi.org/10.14419/ijet.v7i4.6.20478.
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The forgery of digital images became very easy and it’s very difficult to ascertain the authenticity of such images by naked eye. Among the various kinds of image forgeries, image splicing is a frequent and widely used technique. Even though various methods are available to detect image splicing forgery, authors have attempted to provide a novel hybrid method which can yield greater accuracy, sensitivity and specificity. In this method, gray level co-occurrence matrix (GLCM) features are extracted using local binary pattern (LBP) operator on the image and the detection of the splicing forged images among the authentic images is done using the popular pattern recognition algorithms such as combined k-NN (Comb-KNN), back propagation neural network (BPNN) and support vector machine (SVM). The recorded results are also compared with the existing results of the previous studies to ascertain the quality of the results.
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Caba, Lavinia, Laura Florea, Cristina Gug, Daniela Cristina Dimitriu y Eusebiu Vlad Gorduza. "Circular RNA—Is the Circle Perfect?" Biomolecules 11, n.º 12 (24 de noviembre de 2021): 1755. http://dx.doi.org/10.3390/biom11121755.
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Circular RNA (circRNA) is a distinct class of non-coding RNA produced, in principle, using a back-splicing mechanism, conserved during evolution, with increased stability and a tissue-dependent expression. Circular RNA represents a functional molecule with roles in the regulation of transcription and splicing, microRNA sponge, and the modulation of protein–protein interaction. CircRNAs are involved in essential processes of life such as apoptosis, cell cycle, and proliferation. Due to the regulatory role (upregulation/downregulation) in pathogenic mechanisms of some diseases (including cancer), its potential roles as a biomarker or therapeutic target in these diseases were studied. This review focuses on the importance of circular RNA in cancer.
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Dostalova Merkerova, Michaela, David Kundrat, Zdenek Krejcik, Andrea Hrustincova, Iva Trsova, Katarina Szikszai, Monika Kaisrlikova et al. "Circular RNAs in Myelodysplastic Syndromes and Impact of SF3B1 Mutations on Their Expression". Blood 138, Supplement 1 (5 de noviembre de 2021): 2590. http://dx.doi.org/10.1182/blood-2021-149633.
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Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases with a high risk of transformation to acute myeloid leukemia (AML). One of the processes implicated in MDS pathogenesis is RNA splicing. Its alterations are caused by somatic mutations in splicing factor genes. Mutations in SF3B1 (Splicing Factor 3b Subunit 1) gene are the most frequently found mutations in MDS. Circular RNAs (circRNAs) are covalently closed RNAs that are produced by back-splicing process. CircRNAs can regulate multiple biological processes through various molecular mechanisms, such as microRNA sponging. Their deregulation is frequently found in cancer. It is likely that they also contribute to the development of MDS, however, their role in MDS has not been researched yet. Therefore, our aim was to explore circRNA levels in MDS and analyze their association with patient prognosis. We further hypothesized that mutations in splicing factor genes can affect production of circRNAs and thus, we examined circRNA levels with respect to the mutational status. We explored transcriptome of 78 MDS patients, 7 AML patients, and 13 healthy donors using Illumina RNA-seq of total RNA isolated from CD34+ bone marrow cells. To associate circRNA levels with mutational status, Illumina TruSight Myeloid Sequencing Panel Kit examining 54 genes was applied. Of 8,620 circRNAs identified by RNA-seq, 204 circRNAs were deregulated in MDS (e.g., MENTRNL, EBF1, and PPM1L-derived circRNAs) and 246 circRNAs were altered between lower- and higher-risk patients (e.g., CHST15, TMTC2, and PDE3B-derived circRNAs). Most of the progression-related circRNAs (n = 234) showed elevated levels in higher-risk patients, suggesting that the back-splicing process might be stimulated during the disease progression. In MDS patients with SF3B1 mutations, other 40 circRNAs were deregulated (e.g., ZNF91, ZEB1, and ZNF124-derived circRNAs). This circRNA profile was substantially different from the profiles associated with the rest of recurrently mutated splicing factor genes (SRSF2, U2AF1, and ZRSR2). To study alterations in forward- and back-splicing in SF3B1-mutated patients, we examined transcriptional differences on the levels of whole genes, transcript variants, and circRNAs and searched for specificities in transcription within individual gene loci. A set of circRNAs whose levels differed specifically without affecting expression of corresponding forward-spliced mRNAs included several oncology/hematopoiesis-relevant genes (e.g., ATM, CBL, ERCC5, ETV6, FLT3, and MAPK6). Gene loci with changed expression of both, alternative mRNA transcripts and circRNAs, but stable transcription on whole gene level included for example CDK14, KDM1A, and ZEB1. Because ZEB1 (Zinc Finger E-Box Binding Homeobox 1) serves as an essential hematopoietic transcription factor, we focused on ZEB1-derived circRNAs (hsa_circ_0000228 and hsa_circ_0003793) in more detail. We demonstrated that upregulation of these circRNAs is SF3B1-specific and not related to any other clinical or molecular characteristics. Finally, using RNA-seq data from CRISPR/Cas9 edited K562 cells (Liberante FG, et al., Sci Rep. 2019; 9:2678), we confirmed that SF3B1 K700E mutation leads to strong upregulation of ZEB1 circRNAs. To conclude, this is an early report showing for the first time that the levels of specific circRNAs are altered in MDS. We demonstrated that particular circRNAs may have potential to become markers that would contribute to more accurate prognosis of MDS patients. Further, we identified circRNAs with deregulated levels specifically in MDS patients with SF3B1 mutation, suggesting that this mutation affects circRNA production. Supported by GA CR (N20-19162S) and MH CZ-DRO (UHKT, 00023736). Disclosures No relevant conflicts of interest to declare.
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Voellenkle, Perfetti, Carrara, Fuschi, Renna, Longo, Sain et al. "Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1". International Journal of Molecular Sciences 20, n.º 8 (19 de abril de 2019): 1938. http://dx.doi.org/10.3390/ijms20081938.
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Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by “back-splicing”, which is the linking covalently of 3′- and 5′-ends of exons. Thus, circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the DMPK gene which results in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four circRNAs discriminated DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified circRNA dysregulation in DM1 patients.
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Xue, Wei, Xu-Kai Ma y Li Yang. "Fast and furious: insights of back splicing regulation during nascent RNA synthesis". Science China Life Sciences 64, n.º 7 (9 de febrero de 2021): 1050–61. http://dx.doi.org/10.1007/s11427-020-1881-1.
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Robic, Annie y Christa Kühn. "Beyond Back Splicing, a Still Poorly Explored World: Non-Canonical Circular RNAs". Genes 11, n.º 9 (22 de septiembre de 2020): 1111. http://dx.doi.org/10.3390/genes11091111.
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Most of the circRNAs reported to date originate from back splicing of a pre-mRNA, and these exonic circRNAs are termed canonical circRNAs. Our objective was to provide an overview of all other (non-canonical) circRNAs that do not originate from the junction of two exons and to characterize their common properties. Those generated through a failure of intron lariat debranching are the best known, even though studies on them are rare. These circRNAs retain the 2′–5′ bond derived from the intron lariat, and this feature probably explains the difficulties in obtaining efficient reverse transcription through the circular junction. Here, we provide an unprecedented overview of non-canonical circRNAs (lariat-derived intronic circRNAs, sub-exonic circRNAs, intron circles, tricRNAs), which all derive from non-coding sequences. As there are few data suggesting their involvement in cellular regulatory processes, we believe that it is early to propose a general function for circRNAs, even for lariat-derived circRNAs. We suggest that their small size and probably strong secondary structures could be major obstacles to their reliable detection. Nevertheless, we believe there are still several possible ways to advance our knowledge of this class of non-coding RNA.
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Suzuki, Hitoshi, Yoshitsugu Aoki, Toshiki Kameyama, Takashi Saito, Satoru Masuda, Jun Tanihata, Tetsuya Nagata, Akila Mayeda, Shin’ichi Takeda y Toshifumi Tsukahara. "Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot". International Journal of Molecular Sciences 17, n.º 10 (13 de octubre de 2016): 1722. http://dx.doi.org/10.3390/ijms17101722.
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Osborne, Shona L., Claire L. Thomas, Steve Gschmeissner y Giampietro Schiavo. "Nuclear PtdIns(4,5)P2 assembles in a mitotically regulated particle involved in pre-mRNA splicing". Journal of Cell Science 114, n.º 13 (1 de julio de 2001): 2501–11. http://dx.doi.org/10.1242/jcs.114.13.2501.
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Phosphoinositide turnover regulates multiple cellular processes. Compared with their well-known cytosolic roles, limited information is available on the functions of nuclear phosphoinositides. Here, we show that phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2) stably associates with electron-dense particles within the nucleus that resemble interchromatin granule clusters. These PtdIns(4,5)P2-containing structures have a distribution which is cell-cycle dependent and contain components of both the transcriptional and pre-mRNA processing machinery, including RNA polymerase II and the splicing factor SC-35. Immunodepletion and add-back experiments demonstrate that PtdIns(4,5)P2 and associated factors are necessary but not sufficient for pre-mRNA splicing in vitro, indicating a crucial role for PtdIns(4,5)P2-containing complexes in nuclear pre-mRNA processing.
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Li, Xiaohan, Bing Zhang, Fuyu Li, Kequan Yu y Yunfei Bai. "The mechanism and detection of alternative splicing events in circular RNAs". PeerJ 8 (25 de septiembre de 2020): e10032. http://dx.doi.org/10.7717/peerj.10032.
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Circular RNAs (circRNAs) are considered as functional biomolecules with tissue/development-specific expression patterns. Generally, a single gene may generate multiple circRNA variants by alternative splicing, which contain different combinations of exons and/or introns. Due to the low abundance of circRNAs as well as overlapped with their linear counterparts, circRNA enrichment protocol is needed prior to sequencing. Compared with numerous algorithms, which use back-splicing reads for detection and functional characterization of circRNAs, original bioinformatic analyzing tools have been developed to large-scale determination of full-length circRNAs and accurate quantification. This review provides insights into the complexity of circRNA biogenesis and surveys the recent progresses in the experimental and bioinformatic methodologies that focus on accurately full-length circRNAs identification.
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Frydrych Capelari, Érika, Guilherme Cordenonsi da Fonseca, Frank Guzman y Rogerio Margis. "Circular and Micro RNAs from Arabidopsis thaliana Flowers Are Simultaneously Isolated from AGO-IP Libraries". Plants 8, n.º 9 (26 de agosto de 2019): 302. http://dx.doi.org/10.3390/plants8090302.
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Competing endogenous RNAs (ceRNAs) are natural transcripts that can act as endogenous sponges of microRNAs (miRNAs), modulating miRNA action upon target mRNAs. Circular RNAs (circRNAs) are one among the various classes of ceRNAs. They are produced from a process called back-splicing and have been identified in many eukaryotes. In plants, their effective action as a miRNA sponge was not yet demonstrated. To address this question, public mRNAseq data from Argonaute-immunoprecipitation libraries (AGO-IP) of Arabidopsis thaliana flowers were used in association with a bioinformatics comparative multi-method to identify putative circular RNAs. A total of 27,812 circRNAs, with at least two reads at the back-splicing junction, were identified. Further analyses were used to select those circRNAs with potential miRNAs binding sites. As AGO forms a ternary complex with miRNA and target mRNA, targets count in AGO-IP and input libraries were compared, demonstrating that mRNA targets of these miRNAs are enriched in AGO-IP libraries. Through this work, five circRNAs that may function as miRNA sponges were identified and one of them were validated by PCR and sequencing. Our findings indicate that this post-transcriptional regulation can also occur in plants.
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Wang, Xiaolin, Jingxin Li, Xing Bian, Cheng Wu, Jinghan Hua, Shuhui Chang, Tianyi Yu et al. "CircURI1 interacts with hnRNPM to inhibit metastasis by modulating alternative splicing in gastric cancer". Proceedings of the National Academy of Sciences 118, n.º 33 (12 de agosto de 2021): e2012881118. http://dx.doi.org/10.1073/pnas.2012881118.
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Circular RNAs (circRNAs) have emerged as key regulators of human cancers, yet their modes of action in gastric cancer (GC) remain largely unknown. Here, we identified circURI1 back-spliced from exons 3 and 4 of unconventional prefoldin RPB5 interactor 1 (URI1) from circRNA profiling of five-paired human gastric and the corresponding nontumor adjacent specimens (paraGC). CircURI1 exhibits the significantly higher expression in GC compared with paraGC and inhibitory effects on cell migration and invasion in vitro and GC metastasis in vivo. Mechanistically, circURI1 directly interacts with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to modulate alternative splicing of genes, involved in the process of cell migration, thus suppressing GC metastasis. Collectively, our study expands the current knowledge regarding the molecular mechanism of circRNA-mediated cancer metastasis via modulating alternative splicing.
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Zhou, Jian, Yali Chen, Menglin He, Xuehan Li y Rurong Wang. "Role of Circular RNAs in Pulmonary Fibrosis". International Journal of Molecular Sciences 23, n.º 18 (10 de septiembre de 2022): 10493. http://dx.doi.org/10.3390/ijms231810493.
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Pulmonary fibrosis is a chronic progressive form of interstitial lung disease, characterized by the histopathological pattern of usual interstitial pneumonia. Apart from aberrant alterations of protein-coding genes, dysregulation of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs), is crucial to the initiation and progression of pulmonary fibrosis. CircRNAs are single-stranded RNAs that form covalently closed loops without 5′ caps and 3′ tails. Different from canonical splicing of mRNA, they are produced from the back-splicing of precursor mRNAs and have unique biological functions, as well as potential biomedical implications. They function as important gene regulators through multiple actions, including sponging microRNAs and proteins, regulating transcription, and splicing, as well as protein-coding and translation in a cap-independent manner. This review comprehensively summarizes the alteration and functional role of circRNAs in pulmonary fibrosis, with a focus on the involvement of the circRNA in the context of cell-specific pathophysiology. In addition, we discuss the diagnostic and therapeutic potential of targeting circRNA and their regulatory pathway mediators, which may facilitate the translation of recent advances from bench to bedside in the future.
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Artemaki, Pinelopi I., Andreas Scorilas y Christos K. Kontos. "Circular RNAs: A New Piece in the Colorectal Cancer Puzzle". Cancers 12, n.º 9 (31 de agosto de 2020): 2464. http://dx.doi.org/10.3390/cancers12092464.
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Colorectal cancer (CRC) is the third most fatal type of malignancy, worldwide. Despite the advances accomplished in the elucidation of its molecular base and the existing CRC biomarkers introduced in the clinical practice, additional research is required. Circular RNAs (circRNAs) constitute a new RNA type, formed by back-splicing of primary transcripts. They have been discovered during the 1970s but were characterized as by-products of aberrant splicing. However, the modern high-throughput approaches uncovered their widespread expression; therefore, several questions were raised regarding their potential biological roles. During the last years, great progress has been achieved in the elucidation of their functions: circRNAs can act as microRNA sponges, transcription regulators, and interfere with splicing, as well. Furthermore, they are heavily involved in various human pathological states, including cancer, and could serve as diagnostic and prognostic biomarkers in several diseases. Particularly in CRC, aberrant expression of circRNAs has been observed. More specifically, these molecules either inhibit or promote colorectal carcinogenesis by regulating different molecules and signaling pathways. The present review discusses the characteristics and functions of circRNA, prior to analyzing the multifaceted role of these molecules in CRC and their potential value as biomarkers and therapeutic targets.
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Robic, Annie, Julie Demars y Christa Kühn. "In-Depth Analysis Reveals Production of Circular RNAs from Non-Coding Sequences". Cells 9, n.º 8 (30 de julio de 2020): 1806. http://dx.doi.org/10.3390/cells9081806.
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The sequencing of total RNA depleted for ribosomal sequences remains the method of choice for the study of circRNAs. Our objective was to characterize non-canonical circRNAs, namely not originating from back splicing and circRNA produced by non-coding genes. To this end, we analyzed a dataset from porcine testis known to contain about 100 intron-derived circRNAs. Labelling reads containing a circular junction and originating from back splicing provided information on the very small contribution of long non-coding genes to the production of canonical circRNAs. Analyses of the other reads revealed two origins for non-canonical circRNAs: (1) Intronic sequences for lariat-derived intronic circRNAs and intron circles, (2) Mono-exonic genes (mostly non-coding) for either a new type of circRNA (including only part of the exon: sub-exonic circRNAs) or, even more rarely, mono-exonic canonical circRNAs. The most complex set of sub-exonic circRNAs was produced by RNase_MRP (ribozyme RNA). We specifically investigated the intronic circRNA of ATXN2L, which is probably an independently transcribed sisRNA (stable intronic sequence RNA). We may be witnessing the emergence of a new non-coding gene in the porcine genome. Our results are evidence that most non-canonical circRNAs originate from non-coding sequences.
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Babaei, Saeid, Mohan B. Singh y Prem L. Bhalla. "Circular RNAs Repertoire and Expression Profile during Brassica rapa Pollen Development". International Journal of Molecular Sciences 22, n.º 19 (24 de septiembre de 2021): 10297. http://dx.doi.org/10.3390/ijms221910297.
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Circular RNAs (circRNAs) are covalently closed RNA molecules generated by the back-splicing of exons from linear precursor mRNAs. Though various linear RNAs have been shown to play important regulatory roles in many biological and developmental processes, little is known about the role of their circular counterparts. In this study, we performed high-throughput RNA sequencing to delineate the expression profile and potential function of circRNAs during the five stages of pollen development in Brassica rapa. A total of 1180 circRNAs were detected in pollen development, of which 367 showed stage-specific expression patterns. Functional enrichment and metabolic pathway analysis showed that the parent genes of circRNAs were mainly involved in pollen-related molecular and biological processes such as mitotic and meiotic cell division, DNA processes, protein synthesis, protein modification, and polysaccharide biosynthesis. Moreover, by predicting the circRNA–miRNA network from our differentially expressed circRNAs, we found 88 circRNAs with potential miRNA binding sites, suggesting their role in post-transcriptional regulation of the genes. Finally, we confirmed the back-splicing sites of nine selected circRNAs using divergent primers and Sanger sequencing. Our study presents the systematic analysis of circular RNAs during pollen development and forms the basis of future studies for unlocking complex gene regulatory networks underpinning reproduction in flowering plants.
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Metge, Franziska, Lisa F. Czaja-Hasse, Richard Reinhardt y Chistoph Dieterich. "FUCHS—towards full circular RNA characterization using RNAseq". PeerJ 5 (28 de febrero de 2017): e2934. http://dx.doi.org/10.7717/peerj.2934.
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Circular RNAs (circRNAs) belong to a recently re-discovered species of RNA that emerge during RNA maturation through a process called back-splicing. A downstream 5′ splice site is linked to an upstream 3′ splice site to form a circular transcript instead of a canonical linear transcript. Recent advances in next-generation sequencing (NGS) have brought circRNAs back into the focus of many scientists. Since then, several studies reported that circRNAs are differentially expressed across tissue types and developmental stages, implying that they are actively regulated and not merely a by-product of splicing. Though functional studies have shown that some circRNAs could act as miRNA-sponges, the function of most circRNAs remains unknown. To expand our understanding of possible roles of circular RNAs, we propose a new pipeline that could fully characterizes candidate circRNA structure from RNAseq data—FUCHS: FUll CHaracterization of circular RNA using RNA-Sequencing. Currently, most computational prediction pipelines use back-spliced reads to identify circular RNAs. FUCHS extends this concept by considering all RNA-seq information from long reads (typically >150 bp) to learn more about the exon coverage, the number of double break point fragments, the different circular isoforms arising from one host-gene, and the alternatively spliced exons within the same circRNA boundaries. This new knowledge will enable the user to carry out differential motif enrichment and miRNA seed analysis to determine potential regulators during circRNA biogenesis. FUCHS is an easy-to-use Python based pipeline that contributes a new aspect to the circRNA research.
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Bregman, D. B., L. Du, S. van der Zee y S. L. Warren. "Transcription-dependent redistribution of the large subunit of RNA polymerase II to discrete nuclear domains." Journal of Cell Biology 129, n.º 2 (15 de abril de 1995): 287–98. http://dx.doi.org/10.1083/jcb.129.2.287.
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A subpopulation of the largest subunit of RNA polymerase II (Pol II LS) is located in 20-50 discrete subnuclear domains that are closely linked to speckle domains, which store splicing proteins. The speckle-associated fraction of Pol II LS is hyperphosphorylated on the COOH-terminal domain (CTD), and it is highly resistant to extraction by detergents. A diffuse nucleoplasmic fraction of Pol II LS is relatively hypophosphorylated on the CTD, and it is easily extracted by detergents. In transcriptionally active nuclei, speckle bound hyperphosphorylated Pol II LS molecules are distributed in irregularly shaped speckle domains, which appear to be interconnected via a reticular network. When transcription is inhibited, hyperphosphorylated Pol II LS and splicing protein SC35 accumulate in speckle domains, which are transformed into enlarged, dot-like structures lacking interconnections. When cells are released from transcriptional inhibition, Pol IIO and SC35 redistribute back to the interconnected speckle pattern of transcriptionally active cells. The redistribution of Pol II and SC35 is synchronous, reversible, and temperature dependent. It is concluded that: (a) hyperphosphorylation of Pol II LS's CTD is a better indicator of its tight association to discrete subnuclear domains than its transcriptional activity; (b) during states of transcriptional inhibition, hyperphosphorylated Pol II LS can be stored in enlarged speckle domains, which under the light microscope appear to coincide with the storage sites for splicing proteins; and (c) Pol II and splicing proteins redistribute simultaneously according to the overall transcriptional activity of the nucleus.
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Wu, Chao y Jing Luo. "Fabrication and Characteristic of Small-Area Flat Lamp Utilizing Carbon Nanotube Film Cathode". Key Engineering Materials 467-469 (febrero de 2011): 1516–19. http://dx.doi.org/10.4028/www.scientific.net/kem.467-469.1516.
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Using carbon nanotubes (CNTs) film as cathode material, the small-area flat lamp (FL) was sealed and fabricated. And the manufacture process for the whole FL was also presented in detail. The pyrolysis process was adopted to grow CNT film directly over the silicon substrate, and the chromium was deposited on the silicon substrate back surface to form the interface layer. After the sintering process for the screen-printed silver slurry, the patterned cathode electrodes were formed on the cathode back plane surface. Using silver slurry as adhesion material, the silicon substrate would be fixed on the cathode electrode. With the splicing method, the CNT film cathode could also be extended on the flat cathode back plane surface. The fabricated small-area FL using CNT film cathode exhibited better field emission property and high luminance brightness.
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Ni, Lu, Takeshi Yamada, Asako Murata y Kazuhiko Nakatani. "Mismatch binding ligand upregulated back-splicing reaction producing circular RNA in a cellular model". Chemical Communications 58, n.º 22 (2022): 3629–32. http://dx.doi.org/10.1039/d1cc06936e.
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Circular RNAs (circRNA) are covalently-closed single stranded RNAs with potent roles in cells. Here, we demonstrate the feasibility of mediating circRNA production in a model environment via a small molecule: naphthyridine carbamate dimer (NCD).
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Huang, Ying y Qubo Zhu. "Mechanisms Regulating Abnormal Circular RNA Biogenesis in Cancer". Cancers 13, n.º 16 (20 de agosto de 2021): 4185. http://dx.doi.org/10.3390/cancers13164185.
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Circular RNAs (circRNAs), which are a class of endogenous RNA with covalently closed loops, play important roles in epigenetic regulation of gene expression at both the transcriptional and post-transcriptional level. Accumulating evidence demonstrated that numerous circRNAs were abnormally expressed in tumors and their dysregulation was involved in the tumorigenesis and metastasis of cancer. Although the functional mechanisms of many circRNAs have been revealed, how circRNAs are dysregulated in cancer remains elusive. CircRNAs are generated by a “back-splicing” process, which is regulated by different cis-regulatory elements and trans-acting proteins. Therefore, how these cis and trans elements change during tumorigenesis and how they regulate the biogenesis of circRNAs in cancer are two questions that interest us. In this review, we summarized the pathways for the biogenesis of circRNAs; and then illustrated how circRNAs dysregulated in cancer by discussing the changes of cis-regulatory elements and trans-acting proteins that related to circRNA splicing and maturation in cancer.
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Yingxin Huang, Ali Hassan Nawaz, Abrar Hussain y Yubin Li. "CircRNA: Its biogenesis and role in skeletal muscle development". International Journal of Life Science Research Archive 3, n.º 1 (30 de agosto de 2022): 078–84. http://dx.doi.org/10.53771/ijlsra.2022.3.1.0081.
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Previously, circRNAs considered splicing errors during transcription, but recent studies uncovered that circRNA is a new group of noncoding RNAs. CircRNAs are produced through back splicing of pre mRNA and have more stability than linear RNA due to its closed loop structure. Numerous studies have unveiled the regulatory functions of circRNA in various biological mechanisms. Current literature has observed that circRNAs regulate the myogenesis of skeletal muscles through sponging miRNAs or acting as competitive endogenous RNA (CeRNA). Apart from myogenesis, it also regulates the functioning of different proteins at the molecular level and plays a key role during translation or protein encoding. All these facts have opened a new arena of research regarding the regulation of gene expression. This study aims to discuss the research advancements and new developments in the regulatory functions of circRNAs, including the development of skeletal muscle. This study also intends to discuss some newly discovered circRNAs involved in skeletal muscle development, especially in chicken and cattle.
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Ayyildiz, Dilara, Guendalina Bergonzoni, Alan Monziani, Takshashila Tripathi, Jessica Döring, Emanuela Kerschbamer, Francesca Di Leva et al. "CAG repeat expansion in the Huntington’s disease gene shapes linear and circular RNAs biogenesis". PLOS Genetics 19, n.º 10 (13 de octubre de 2023): e1010988. http://dx.doi.org/10.1371/journal.pgen.1010988.
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Alternative splicing (AS) appears to be altered in Huntington’s disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, a significant proportion (36%) of the aberrantly spliced isoforms are not-functional and meant to non-sense mediated decay (NMD). The expanded Htt CAG repeats further reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Integrative transcriptomic analyses unveil a network of transcriptionally altered micro-RNAs and RNA-binding proteins (CELF, hnRNPS, PTBP, SRSF, UPF1, YTHD2) which might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might alter neural fitness, contributing to HD pathogenesis.
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Xiao, Juan, Shija Joseph, Mengwei Xia, Feng Teng, Xuejiao Chen, Rufeng Huang, Lihong Zhai y Wenbin Deng. "Circular RNAs Acting as miRNAs’ Sponges and Their Roles in Stem Cells". Journal of Clinical Medicine 11, n.º 10 (20 de mayo de 2022): 2909. http://dx.doi.org/10.3390/jcm11102909.
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Circular RNAs (circRNAs), a novel type of endogenous RNAs, have become a subject of intensive research. It has been found that circRNAs are important players in cell differentiation and tissue homeostasis, as well as disease development. Moreover, the expression of circRNAs is usually not correlated with their parental gene expression, indicating that they are not only a steady-state by-product of mRNA splicing but a product of variable splicing under novel regulation. Sequence conservation analysis has also demonstrated that circRNAs have important non-coding functions. CircRNAs exist as a covalently closed loop form in mammalian cells, where they regulate cellular transcription and translation processes. CircRNAs are built from pre-messenger RNAs, and their biogenesis involves back-splicing, which is catalyzed by spliceosomes. The splicing reaction gives rise to three different types of intronic, exotic and exon–intron circular RNAs. Due to higher nuclease stability and longer half lives in cells, circRNAs are more stable than linear RNAs and have enormous clinical advantage for use as diagnostic and therapeutic biomarkers for disease. In recent years, it has been reported that circRNAs in stem cells play a crucial role in stem cell function. In this article, we reviewed the general feature of circRNAs and the distinct roles of circRNAs in stem cell biology, including regulation of stem cell self-renewal and differentiation. CircRNAs have shown unique expression profiles during differentiation of stem cells and could serve as promising biomarkers of these cells. As circRNAs play pivotal roles in stem cell regulation as well as the development and progression of various diseases, we also discuss opportunities and challenges of circRNA-based treatment strategies in future effective therapies for promising clinical applications.
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Yuan, Haomiao, Xizhou Liao, Ding Hu, Dawei Guan y Meihui Tian. "Back to the Origin: Mechanisms of circRNA-Directed Regulation of Host Genes in Human Disease". Non-Coding RNA 10, n.º 5 (24 de septiembre de 2024): 49. http://dx.doi.org/10.3390/ncrna10050049.
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Circular RNAs (circRNAs) have been shown to be pivotal regulators in various human diseases by participating in gene splicing, acting as microRNA (miRNA) sponges, interacting with RNA-binding proteins (RBPs), and translating into short peptides. As the back-splicing products of pre-mRNAs, many circRNAs can modulate the expression of their host genes through transcriptional, post-transcriptional, translational, and post-translational control via interaction with other molecules. This review provides a detailed summary of these regulatory mechanisms based on the class of molecules that they interact with, which encompass DNA, mRNA, miRNA, and RBPs. The co-expression of circRNAs with their parental gene productions (including linear counterparts and proteins) provides potential diagnostic biomarkers for multiple diseases. Meanwhile, the different regulatory mechanisms by which circRNAs act on their host genes via interaction with other molecules constitute complex regulatory networks, which also provide noticeable clues for therapeutic strategies against diseases. Future research should explore whether these proven mechanisms can play a similar role in other types of disease and clarify further details about the cross-talk between circRNAs and host genes. In addition, the regulatory relationship between circRNAs and their host genes in circRNA circularization, degradation, and cellular localization should receive further attention.
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Lakiotaki, Eleftheria, Dimitrios Kanakoglou, Andromachi Pampalou, Eleni Karatrasoglou, Christina Piperi y Penelope Korkolopoulou. "Dissecting the Role of Circular RNAs in Sarcomas with Emphasis on Osteosarcomas". Biomedicines 9, n.º 11 (8 de noviembre de 2021): 1642. http://dx.doi.org/10.3390/biomedicines9111642.
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Circular RNAs (circRNAs) are single-stranded RNAs generated from exons back-splicing from a single pre-mRNA, forming covalently closed loop structures which lack 5′-3′-polarity or polyadenylated tail. Ongoing research depicts that circRNAs play a pivotal role in tumorigenesis, tumor progression, metastatic potential and chemoresistance by regulating transcription, microRNA (miRNA) sponging, RNA-binding protein interactions, alternative splicing and to a lesser degree, protein coding. Sarcomas are rare malignant tumors stemming from mesenchymal cells. Due to their clinically insidious onset, they often present at advanced stage and their treatment may require aggressive chemotherapeutic or surgical options. This review is mainly focused on the regulatory functions of circRNAs on osteosarcoma progression and their potential role as biomarkers, an area which has prompted lately extensive research. The attributed oncogenic role of circRNAs on other mesenchymal tumors such as Kaposi Sarcoma (KS), Rhabdomyosarcoma (RMS) or Gastrointestinal Stromal Tumors (GISTs) is also described. The involvement of circRNAs on sarcoma oncogenesis and relevant emerging diagnostic, prognostic and therapeutic applications are expected to gain more research interest in the future.
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Choi, Sae Seul, Sae Eun Kim, Seon Young Oh y Young-Ho Ahn. "Clinical Implications of Circulating Circular RNAs in Lung Cancer". Biomedicines 10, n.º 4 (8 de abril de 2022): 871. http://dx.doi.org/10.3390/biomedicines10040871.
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Circular RNAs (circRNAs) are single-stranded RNAs with a covalently closed-loop structure that increases their stability; thus, they are more advantageous to use as liquid biopsy markers than linear RNAs. circRNAs are thought to be generated by back-splicing of pre-mRNA transcripts, which can be facilitated by reverse complementary sequences in the flanking introns and trans-acting factors, such as splicing regulatory factors and RNA-binding factors. circRNAs function as miRNA sponges, interact with target proteins, regulate the stability and translatability of other mRNAs, regulate gene expression, and produce microproteins. circRNAs are also found in the body fluids of cancer patients, including plasma, saliva, urine, and cerebrospinal fluid, and these “circulating circRNAs” can be used as cancer biomarkers. In lung cancer, some circulating circRNAs have been reported to regulate cancer progression and drug resistance. Circulating circRNAs have significant diagnostic value and are associated with the prognosis of lung cancer patients. Owing to their functional versatility, heightened stability, and practical applicability, circulating circRNAs represent promising biomarkers for lung cancer diagnosis, prognosis, and treatment monitoring.
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Ho-Xuan, Hung, Petar Glažar, Claudia Latini, Kevin Heizler, Jacob Haase, Robert Hett, Marvin Anders et al. "Comprehensive analysis of translation from overexpressed circular RNAs reveals pervasive translation from linear transcripts". Nucleic Acids Research 48, n.º 18 (21 de septiembre de 2020): 10368–82. http://dx.doi.org/10.1093/nar/gkaa704.
Texto completoResumen
Abstract Circular RNAs (circRNAs) encompass a widespread and conserved class of RNAs, which are generated by back-splicing of downstream 5′ to upstream 3′ splice sites. CircRNAs are tissue-specific and have been implicated in diseases including cancer. They can function as sponges for microRNAs (miRNAs) or RNA binding proteins (RBPs), for example. Moreover, some contain open reading frames (ORFs) and might be translated. The functional relevance of such peptides, however, remains largely elusive. Here, we report that the ORF of circZNF609 is efficiently translated when expressed from a circZNF609 overexpression construct. However, endogenous proteins could not be detected. Moreover, initiation of circZNF609 translation is independent of m6A-generating enzyme METTL3 or RNA sequence elements such as internal ribosome entry sites (IRESs). Surprisingly, a comprehensive mutational analysis revealed that deletion constructs, which are deficient in producing circZNF609, still generate the observed protein products. This suggests that the apparent circZNF609 translation originates from trans-splicing by-products of the overexpression plasmids and underline that circRNA overexpression constructs need to be evaluated carefully, particularly when functional studies are performed.
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Hou, Li-Dan y Jing Zhang. "Circular RNAs: An emerging type of RNA in cancer". International Journal of Immunopathology and Pharmacology 30, n.º 1 (30 de enero de 2017): 1–6. http://dx.doi.org/10.1177/0394632016686985.
Texto completoResumen
Circular RNAs (circRNAs), a novel type of widespread and diverse endogenous non-coding RNAs (ncRNAs), which are different from the linear RNAs, form a covalently closed continuous loop without 5’ or 3’ polarities. The majority of circRNAs are abundant, conserved and stable across different species, and exhibit tissue/developmental-stage-specific characteristics. They are generated primarily through a type of alternative RNA splicing called “back-splicing,” in which a downstream splice donor is joined to an upstream splice acceptor through splice skipping or direct splice. Recent studies have discovered circRNAs function as microRNA sponges, binding with RNA-associated proteins to form RNA–protein complexes and then regulating gene transcription and translation into polypeptides. Emerging evidence indicates that circRNAs play important roles in the regulation of the development and progression of multiple cancers by serving as potential diagnostic and predictive biomarkers involved in tumor growth and invasion and providing new strategies for cancer diagnosis and targeted therapy. In this review, we briefly delineate the diversity and characteristics of circRNAs and discuss the highlights of the biogenesis of circRNAs and their potential functions in tumor.
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Shomron, Noam, Mika Reznik y Gil Ast. "Splicing Factor hSlu7 Contains a Unique Functional Domain Required to Retain the Protein within the Nucleus". Molecular Biology of the Cell 15, n.º 8 (agosto de 2004): 3782–95. http://dx.doi.org/10.1091/mbc.e04-02-0152.
Texto completoResumen
Precursor-mRNA splicing removes the introns and ligates the exons to form a mature mRNA. This process is carried out in a spliceosomal complex containing >150 proteins and five small nuclear ribonucleoproteins. Splicing protein hSlu7 is required for correct selection of the 3′ splice site. Here, we identify by bioinformatics and mutational analyses three functional domains of the hSlu7 protein that have distinct roles in its subcellular localization: a nuclear localization signal, a zinc-knuckle motif, and a lysine-rich region. The zinc-knuckle motif is embedded within the nuclear localization signal in a unique functional structure that is not required for hSlu7's entrance into the nucleus but rather to maintain hSlu7 inside it, preventing its shuttle back to the cytoplasm via the chromosomal region maintenance 1 pathway. Thus, the zinc-knuckle motif of hSlu7 determines the cellular localization of the protein through a nucleocytoplasmic-sensitive shuttling balance. Altogether, this indicates that zinc-dependent nucleocytoplasmic shuttling might be the possible molecular basis by which hSlu7 protein levels are regulated within the nucleus.