Nuclear Rna
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2021 ◽  
Vol 17 (9) ◽  
pp. e1009947
Mingzhu Ding ◽  
Jinfeng Wu ◽  
Rui Sun ◽  
Lijun Yan ◽  
Lei Bai ◽  

Kaposi’s sarcoma-associated herpesvirus (KSHV) preferentially infects and causes Kaposi’s sarcoma (KS) in male patients. However, the biological mechanisms are largely unknown. This study was novel in confirming the extensive nuclear distribution of the androgen receptor (AR) and its co-localization with viral oncoprotein of latency-associated nuclear antigen in KS lesions, indicating a transcription way of AR in KS pathogenesis. The endogenous AR was also remarkably higher in KSHV-positive B cells than in KSHV-negative cells and responded to the ligand treatment of 5α-dihydrotestosterone (DHT), the agonist of AR. Then, the anti-AR antibody-based chromatin immunoprecipitation (ChIP)-associated sequencing was used to identify the target viral genes of AR, revealing that the AR bound to multiple regions of lytic genes in the KSHV genome. The highest peak was enriched in the core promoter sequence of polyadenylated nuclear RNA (PAN), and the physical interaction was verified by ChIP–polymerase chain reaction (PCR) and the electrophoretic mobility shift assay (EMSA). Consistently, male steroid treatment significantly transactivated the promoter activity of PAN in luciferase reporter assay, consequently leading to extensive lytic gene expression and KSHV production as determined by real-time quantitative PCR, and the deletion of nuclear localization signals of AR resulted in the loss of nuclear transport and transcriptional activity in the presence of androgen and thus impaired the expression of PAN RNA. Oncogenically, this study identified that the AR was a functional prerequisite for cell invasion, especially under the context of KSHV reactivation, through hijacking the PAN as a critical effector. Taken together, a novel mechanism from male sex steroids to viral noncoding RNA was identified, which might provide a clue to understanding the male propensity in KS.

2021 ◽  
Gabrielle Deschamps-Francoeur ◽  
Sonia Couture ◽  
Sherif Abou Elela ◽  
Michelle S Scott

Box C/D small nucleolar RNAs (snoRNAs) are a conserved class of noncoding RNA known to serve as guides for the site-specific 2'-O-ribose methylation of ribosomal RNAs and the U6 small nuclear RNA, through direct base pairing with the target. In recent years however, several examples of box C/D snoRNAs regulating different levels of gene expression including transcript stability and splicing have been reported. These regulatory interactions typically require direct binding of the target but do not always involve the guide region. Supporting these new box C/D snoRNA functions, high-throughput RNA-RNA interaction datasets detect many interactions between box C/D snoRNAs and messenger RNAs. To facilitate the study of box C/D snoRNA functionality, we created snoGloBe, a box C/D snoRNA machine learning target predictor based on a gradient boosting classifier and considering snoRNA and target sequence and position as well as target type. SnoGloBe convincingly outperforms general RNA duplex predictors and PLEXY, the only box C/D snoRNA-specific target predictor available. The study of snoGloBe human transcriptome-wide predictions identifies enrichment in snoRNA interactions in exons and on exon-intron junctions. Some specific snoRNAs are predicted to target groups of functionally-related transcripts on common regulatory elements and the exact position of the predicted targets strongly overlaps binding sites of RNA-binding proteins involved in relevant molecular functions. SnoGloBe was also applied to predicting interactions between human box C/D snoRNAs and the SARS-CoV-2 transcriptome, identifying known and novel interactions. Overall, snoGloBe is a timely new tool that will accelerate our understanding of C/D snoRNA targets and function.

2021 ◽  
Andrew Loffer ◽  
Jasleen Singh ◽  
Akihito Fukudome ◽  
Vibhor Mishra ◽  
Feng Wang ◽  

In plants, selfish genetic elements including retrotransposons and DNA viruses are transcriptionally silenced by RNA-directed DNA methylation. Guiding the process are short interfering RNAs (siRNAs) cut by DICER-LIKE 3 (DCL3) from double-stranded precursors of ~30 bp synthesized by NUCLEAR RNA POLYMERASE IV (Pol IV) and RNA-DEPENDENT RNA POLYMERASE 2 (RDR2). We show that Pol IV initiating nucleotide choice, RDR2 initiation 1-2 nt internal to Pol IV transcript ends and RDR2 terminal transferase activity collectively yield a code that influences which end of the precursor is diced and whether 24 or 23 nt siRNAs are generated from the Pol IV or RDR2-transcribed strands. By diversifying the size, sequence, and strand polarity of siRNAs derived from a given precursor, alternative patterns of DCL3 dicing allow maximal siRNA coverage at methylated target loci.

2021 ◽  
Kunpeng Liu ◽  
Qianwen Sun

Abstract Eukaryotic genomes are transcribed by at least three RNA polymerases, RNAPI, II, and III. Co-transcriptional R-loops play diverse roles in genome regulation and maintenance. However, little is known about how R-loops regulate transcription interference, the transcriptional event that is caused by different RNA polymerases transcribing the same genomic templates. Here, we established that the intragenic tRNA genes can promote sense R-loop enrichment (named intra-tR-loops) in Arabidopsis thaliana, and found that intra-tR-loops are decreased in an RNAPIII mutant, nrpc7-1 (NUCLEAR RNA POLYMERASE C, SUBUNIT 7). NRPC7 is co-localized with RNAPIIS2P at intragenic tRNA genes and interferes with RNAPIIS2P elongation. Conversely, the binding of NRPC7 at intragenic tRNA genes is increased following inhibition of RNAPII elongation. The transcription of specific tRNA host genes is inhibited by RNAPIII, and the inhibition of tRNA host genes is intra-tR-loop dependent. Moreover, alleviating the inhibition of tRNAPro-induced intra-tR-loops on its host gene AtNUDX1 (Arabidopsis Nudix hydrolase 1) promotes oxidative stress tolerance in Arabidopsis thaliana. Our work suggests intra-tR-loops regulate host gene expression by modulating RNA polymerases interference.

2021 ◽  
Vol 22 (1) ◽  
Duy Nguyen ◽  
Nicolas Buisine ◽  
Olivier Fayol ◽  
Annemieke A. Michels ◽  
Olivier Bensaude ◽  

Abstract Background The 7SK small nuclear RNA (snRNA) found in most metazoans is a key regulator of P-TEFb which in turn regulates RNA polymerase II elongation. Although its primary sequence varies in protostomes, its secondary structure and function are conserved across evolutionary distant taxa. Results Here, we describe a novel ncRNA sharing many features characteristic of 7SK RNAs, in D. melanogaster. We examined the structure of the corresponding gene and determined the expression profiles of the encoded RNA, called snRNA:7SK:94F, during development. It is probably produced from the transcription of a lncRNA which is processed into a mature snRNA. We also addressed its biological function and we show that, like dm7SK, this alternative 7SK interacts in vivo with the different partners of the P-TEFb complex, i.e. HEXIM, LARP7 and Cyclin T. This novel RNA is widely expressed across tissues. Conclusion We propose that two distinct 7SK genes might contribute to the formation of the 7SK snRNP complex in D. melanogaster.

2021 ◽  
Vol 9 (9) ◽  
pp. 1794
Mansi Srivastava ◽  
Dwight Hall ◽  
Okiemute Beatrice Omoru ◽  
Hunter Mathias Gill ◽  
Sarah Smith ◽  

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid evolution has led to a global health crisis. Increasing mutations across the SARS-CoV-2 genome have severely impacted the development of effective therapeutics and vaccines to combat the virus. However, the new SARS-CoV-2 variants and their evolutionary characteristics are not fully understood. Host cellular components such as the ACE2 receptor, RNA-binding proteins (RBPs), microRNAs, small nuclear RNA (snRNA), 18s rRNA, and the 7SL RNA component of the signal recognition particle (SRP) interact with various structural and non-structural proteins of the SARS-CoV-2. Several of these viral proteins are currently being examined for designing antiviral therapeutics. In this review, we discuss current advances in our understanding of various host cellular components targeted by the virus during SARS-CoV-2 infection. We also summarize the mutations across the SARS-CoV-2 genome that directs the evolution of new viral strains. Considering coronaviruses are rapidly evolving in humans, this enables them to escape therapeutic therapies and vaccine-induced immunity. In order to understand the virus’s evolution, it is essential to study its mutational patterns and their impact on host cellular machinery. Finally, we present a comprehensive survey of currently available databases and tools to study viral–host interactions that stand as crucial resources for developing novel therapeutic strategies for combating SARS-CoV-2 infection.

2021 ◽  
Vol 11 (1) ◽  
Parameet Kumar ◽  
Dharmendra Kumar Soni ◽  
Chaitali Sen ◽  
Mads B. Larsen ◽  
Krystyna Mazan-Mamczarz ◽  

AbstractCystic fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.

AnnaMaria Maraschi ◽  
Valentina Gumina ◽  
Jessica Dragotto ◽  
Claudia Colombrita ◽  
Miguel Mompeán ◽  

AbstractThe nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106–110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

2021 ◽  
Tomas Zelenka ◽  
Petros Tzerpos ◽  
Giorgos Panagopoulos ◽  
Konstantinos Tsolis ◽  
Dionysios-Alexandros Papamatheakis ◽  

Intracellular space is demarcated into functional membraneless organelles and nuclear bodies via the process of phase separation. Phase transitions are involved in many functions linked to such bodies as well as in gene expression regulation and other cellular processes. In this work we describe how the genome organizer SATB1 utilizes its prion-like domains to undergo phase transitions. We have identified two SATB1 isoforms with distinct biophysical behavior and showed how phosphorylation and interaction with nuclear RNA, impact their phase transitions. Moreover, we show that SATB1 is associated with transcription and splicing, both of which evinced deregulation in Satb1 knockout mice. Thus, the tight regulation of different SATB1 isoforms levels and their post-translational modifications are imperative for SATB1's physiological roles in T cell development while their deregulation may be linked to disorders such as cancer.

Nature ◽  
2021 ◽  
Zhenwei Zhang ◽  
Norbert Rigo ◽  
Olexandr Dybkov ◽  
Jean-Baptiste Fourmann ◽  
Cindy L. Will ◽  

AbstractDuring the splicing of introns from precursor messenger RNAs (pre-mRNAs), the U2 small nuclear ribonucleoprotein (snRNP) must undergo stable integration into the spliceosomal A complex—a poorly understood, multistep process that is facilitated by the DEAD-box helicase Prp5 (refs. 1–4). During this process, the U2 small nuclear RNA (snRNA) forms an RNA duplex with the pre-mRNA branch site (the U2–BS helix), which is proofread by Prp5 at this stage through an unclear mechanism5. Here, by deleting the branch-site adenosine (BS-A) or mutating the branch-site sequence of an actin pre-mRNA, we stall the assembly of spliceosomes in extracts from the yeast Saccharomyces cerevisiae directly before the A complex is formed. We then determine the three-dimensional structure of this newly identified assembly intermediate by cryo-electron microscopy. Our structure indicates that the U2–BS helix has formed in this pre-A complex, but is not yet clamped by the HEAT domain of the Hsh155 protein (Hsh155HEAT), which exhibits an open conformation. The structure further reveals a large-scale remodelling/repositioning of the U1 and U2 snRNPs during the formation of the A complex that is required to allow subsequent binding of the U4/U6.U5 tri-snRNP, but that this repositioning is blocked in the pre-A complex by the presence of Prp5. Our data suggest that binding of Hsh155HEAT to the bulged BS-A of the U2–BS helix triggers closure of Hsh155HEAT, which in turn destabilizes Prp5 binding. Thus, Prp5 proofreads the branch site indirectly, hindering spliceosome assembly if branch-site mutations prevent the remodelling of Hsh155HEAT. Our data provide structural insights into how a spliceosomal helicase enhances the fidelity of pre-mRNA splicing.

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