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Rna induced silencing complex

Philipp Michael Klein, Sören Reinhard, Dian-Jang Lee, Katharina Müller, Daniela Ponader, Laura Hartmann, Ernst Wagner
Lipo-oligomers have been proven as potent siRNA carriers based on stable electrostatic and hydrophobic complex formation and endosomal membrane destabilization. Although high stability of siRNA polyplexes is desirable in the extracellular space and cellular uptake, intracellular disassembly is important for the cytosolic release of siRNA and RNA-induced silencing complex formation. To improve the release, bioreducible sequence-defined lipo-oligomers were synthesized by solid-phase assisted synthesis using the disulfide building block Fmoc-succinoyl-cystamine for precise positioning of a disulfide unit between a lipophilic diacyl (bis-myristyl, bis-stearyl or bis-cholestanyl) domain and an ionizable oligocationic siRNA binding unit...
October 13, 2016: Nanoscale
Jisoo Shin, Jung Ho Cho, Yoonhee Jin, Kisuk Yang, Jong Seung Lee, Hyun-Ji Park, Hyung-Seop Han, Jinkyu Lee, Hojeong Jeon, Heungsoo Shin, Seung-Woo Cho
Using small interfering RNA (siRNA) to regulate gene expression is an emerging strategy for stem cell manipulation to improve stem cell therapy. However, conventional methods of siRNA delivery into stem cells based on solution-mediated transfection are limited due to low transfection efficiency and insufficient duration of cell-siRNA contact during lengthy culturing protocols. To overcome these limitations, a bio-inspired polymer-mediated reverse transfection system is developed consisting of implantable poly(lactic-co-glycolic acid) (PLGA) scaffolds functionalized with siRNA-lipidoid nanoparticle (sLNP) complexes via polydopamine (pDA) coating...
September 26, 2016: Small
Yibei Xiao, Ailong Ke
piRNA guides the action of PIWI proteins to silence deleterious transposons in animal reproductive tissues. Biogenesis of piRNA-induced silencing complex (piRISC) involves a multi-step process. In this issue, Matsumoto et al. report the first crystal structure of a PIWI-clade protein displaying a guide RNA, ready for action.
October 6, 2016: Cell
David S Rabiger, Jennifer M Taylor, Andrew Spriggs, Melanie L Hand, Steven T Henderson, Susan D Johnson, Karsten Oelkers, Maria Hrmova, Keisuke Saito, Go Suzuki, Yasuhiko Mukai, Bernard J Carroll, Anna M G Koltunow
BACKGROUND: Application of apomixis, or asexual seed formation, in crop breeding would allow rapid fixation of complex traits, economizing improved crop delivery. Identification of apomixis genes is confounded by the polyploid nature, high genome complexity and lack of genomic sequence integration with reproductive tissue transcriptomes in most apomicts. RESULTS: A genomic and transcriptomic resource was developed for Hieracium subgenus Pilosella (Asteraceae) which incorporates characterized sexual, apomictic and mutant apomict plants exhibiting reversion to sexual reproduction...
October 6, 2016: BMC Biology
Aleksandra Poterala, Joanna Rzeszowska-Wolny
Ago proteins are members of the highly specialized and conserved Argonaute family, primarily responsible for regulation of gene expression. As a part of RNA-induced silencing complexes (RISCs) Ago proteins are responsible for binding a short RNA and cleavage/inhibition of translation of target mRNAs. Phosphorylation may work as the switch between those two functions, but the role of magnesium ion concentration is also taken into consideration. Recent reports indicate that Ago proteins can interact with an mRNA and cause inhibition of translation without the participation of a short RNA...
September 28, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
Moran Golan, Valeria Feinshtein, Ayelet David
The key for successful gene silencing is to design a safe and efficient siRNA delivery system for the transfer of therapeutic nucleic acids into the target cells. Here, we describe the design of hydrophilic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer displaying multiple copies of octaarginine (R8) and its use in promoting the effective delivery of small interfering RNA (siRNA) molecules intracellularly. Fluorescein-5-isothiocyanate (FITC)-labeled HPMA copolymer-bound R8 (P-R8-FITC) was synthesized with increasing R8 molar ratios (4 to 9...
October 1, 2016: European Journal of Pharmaceutics and Biopharmaceutics
Matthew A Lafreniere, Megan H Powdrill, Ragunath Singaravelu, John Paul Pezacki
Many viruses, including the hepatitis C virus (HCV), are dependent on the host RNA silencing pathway for replication. In this study, we screened small molecule probes, previously reported to disrupt loading of the RNA-induced silencing complex (RISC), including 6-hydroxydopamine (6-OHDA), suramin (SUR), and aurintricarboxylic acid (ATA), to examine their effects on viral replication. We found that 6-OHDA inhibited HCV replication; however, 6-OHDA was a less potent inhibitor of RISC than either SUR or ATA. By generating a novel chemical probe (6-OHDA-yne), we determined that 6-OHDA covalently modifies host and virus proteins...
October 13, 2016: ACS Infectious Diseases
Christina Gross, Xiaodi Yao, Tobias Engel, Durgesh Tiwari, Lei Xing, Shane Rowley, Scott W Danielson, Kristen T Thomas, Eva M Jimenez-Mateos, Lindsay M Schroeder, Raymund Y K Pun, Steve C Danzer, David C Henshall, Gary J Bassell
Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4...
September 27, 2016: Cell Reports
Davide S Sardina, Salvatore Alaimo, Alfredo Ferro, Alfredo Pulvirenti, Rosalba Giugno
Posttranscriptional cross talk and communication between genes mediated by microRNA response element (MREs) yield large regulatory competing endogenous RNA (ceRNA) networks. Their inference may improve the understanding of pathologies and shed new light on biological mechanisms. A variety of RNA: messenger RNA, transcribed pseudogenes, noncoding RNA, circular RNA and proteins related to RNA-induced silencing complex complex interacting with RNA transfer and ribosomal RNA have been experimentally proved to be ceRNAs...
September 26, 2016: Briefings in Bioinformatics
Katsunori Murota, Hanako Shimura, Minoru Takeshita, Chikara Masuta
Cucumber mosaic virus (CMV) can induce a specific necrosis on Arabidopsis through the interaction between the CMV 2b protein and host catalase, in which the ubiquitin-proteasome pathway may be involved. We previously reported that the CMV 2b protein, the viral RNA silencing suppressor, interacted with the H2O2 scavenger catalase (CAT3), leading to necrosis on CMV-inoculated Arabidopsis leaves. We here confirmed that CMV could more abundantly accumulate in the CAT3-knockout mutant (cat3), and that CAT3 makes host plants a little more tolerant to CMV...
September 22, 2016: Plant Cell Reports
Vladimir S Trubetskoy, Jacob B Griffin, Anthony L Nicholas, Eric M Nord, Zhao Xu, Ryan M Peterson, Christine I Wooddell, David B Rozema, Darren H Wakefield, David L Lewis, Steven B Kanner
The RNA interference (RNAi)-based therapeutic ARC-520 for chronic hepatitis B virus (HBV) infection consists of a melittin-derived peptide conjugated to N-acetylgalactosamine for hepatocyte targeting and endosomal escape, and cholesterol-conjugated RNAi triggers, which together result in HBV gene silencing. To characterize the kinetics of RNAi trigger delivery and 5'-phosphorylation of guide strands correlating with gene knockdown, we employed a peptide-nucleic acid (PNA) hybridization assay. A fluorescent sense strand PNA probe binding to RNAi duplex guide strands was coupled with anion exchange high performance liquid chromatography to quantitate guide strands and metabolites...
September 19, 2016: Nucleic Acids Research
Anthony Sanchez, Angelo De Vivo, Nadima Uprety, Jonghwan Kim, Stanley M Stevens, Younghoon Kee
BMI1 is a component of the Polycomb Repressive Complex 1 (PRC1), which plays a key role in maintaining epigenetic silencing during development. BMI1 also participates in gene silencing during DNA damage response, but the precise downstream function of BMI1 in gene silencing is unclear. Here we identified the UBR5 E3 ligase as a downstream factor of BMI1. We found that UBR5 forms damage-inducible nuclear foci in a manner dependent on the PRC1 components BMI1, RNF1 (RING1a), and RNF2 (RING1b). Whereas transcription is repressed at UV-induced lesions on chromatin, depletion of the PRC1 members or UBR5 alone derepressed transcription elongation at these sites, suggesting that UBR5 functions in a linear pathway with PRC1 in inducing gene silencing at lesions...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sampurna Sattar, Gary A Thompson
Non-coding small RNAs (sRNAs) in plants have important roles in regulating biological processes, including development, reproduction, and stress responses. Recent research indicates significant roles for sRNA-mediated gene silencing during plant-hemipteran interactions that involve all three of these biological processes. Plant responses to hemipteran feeding are determined by changes in the host transcriptome that appear to be fine-tuned by sRNAs. The role of sRNA in plant defense responses is complex. Different forms of sRNAs, with specific modes of action, regulate changes in the host transcriptome primarily through post-transcriptional gene silencing and occasionally through translational repression...
2016: Frontiers in Plant Science
Osama Garwain, Suzanne Scarlata
When treated with nerve growth factor (NGF), PC12 cells will differentiate over the course of several days. Here, we have followed changes during differentiation in the cellular levels of phosphoinositide-specific-phospholipase Cβ (PLCβ) and its activator, Gαq, which together mediate Ca(2+) release. We also followed changes in the level of the novel PLCPLCβ binding partner TRAX (translin-associated factor X) which promotes RNA-induced gene silencing. We find that the level of PLCPLCβ increases 4-fold within 24 hrs while Gαq increases only 1...
September 12, 2016: Journal of Biological Chemistry
Elizabeth J F White, Aerielle E Matsangos, Gerald M Wilson
AUF1 is a family of four RNA-binding proteins (RBPs) generated by alternative pre-messenger RNA (pre-mRNA) splicing, with canonical roles in controlling the stability and/or translation of mRNA targets based on recognition of AU-rich sequences within mRNA 3' untranslated regions. However, recent studies identifying AUF1 target sites across the transcriptome have revealed that these canonical functions are but a subset of its roles in posttranscriptional regulation of gene expression. In this review, we describe recent developments in our understanding of the RNA-binding properties of AUF1 together with their biochemical implications and roles in directing mRNA decay and translation...
September 13, 2016: Wiley Interdisciplinary Reviews. RNA
Nicolas Melis, Isabelle Rubera, Marc Cougnon, Sébastien Giraud, Baharia Mograbi, Amine Belaid, Didier F Pisani, Stephan M Huber, Sandra Lacas-Gervais, Konstantina Fragaki, Nicolas Blondeau, Paul Vigne, Christian Frelin, Thierry Hauet, Christophe Duranton, Michel Tauc
The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of Drosophila during long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia...
September 9, 2016: Journal of the American Society of Nephrology: JASN
Noah I Hornick, Ben Doron, Sherif Abdelhamed, Jianya Huan, Christina A Harrington, Rongkun Shen, Xiaolu A Cambronne, Santhosh Chakkaramakkil Verghese, Peter Kurre
Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors. We found that the systemic loss of hematopoietic function is also in part a consequence of AML exosome-directed microRNA (miRNA) trafficking to HSPCs. Exosomes isolated from cultured AML or the plasma from mice bearing AML xenografts exhibited enrichment of miR-150 and miR-155...
2016: Science Signaling
Michitaka Oho, Risa Nakano, Ryutarou Nakayama, Wataru Sakurai, Azusa Miyamoto, Yoshikazu Masuhiro, Shigemasa Hanazawa
TNF-α-induced protein 8-like 2 (TIPE2) is a novel death-effector domain (DED) protein and is a negative regulator of the innate and adaptive immune response. Although it has been demonstrated that caspase-8 contributes to the negative regulation of TIPE2, the negative regulatory mechanism is not entirely understood. Here, we demonstrate that TIPE2 interacts with TGF-β-activated kinase 1 (TAK1), a crucial regulatory molecule of inflammatory and immune signals, and consequently acts as a powerful negative regulator of TAK1...
September 6, 2016: Journal of Biological Chemistry
Jing Zhang, Hehua Liu, Qingqing Yao, Xiang Yu, Yiqing Chen, Ruixue Cui, Baixing Wu, Lina Zheng, Junjun Zuo, Zhen Huang, Jinbiao Ma, Jianhua Gan
Translin and translin-associated factor-x are highly conserved in eukaroytes; they can form heteromeric complexes (known as C3POs) and participate in various nucleic acid metabolism pathways. In humans and Drosophila, C3POs cleave the fragmented siRNA passenger strands and facilitate the activation of RNA-induced silencing complex, the effector complex of RNA interference (RNAi). Here, we report three crystal structures of Nanoarchaeum equitans (Ne) C3PO. The apo-NeC3PO structure adopts an open form and unravels a potential substrates entryway for the first time...
September 4, 2016: Nucleic Acids Research
Jialin Song, Yinghui Chen, Shichao Jiang, Kejia Yang, Xiaoming Li, Xiaotian Zhao, Yuanming Ouyang, Cunyi Fan, Weien Yuan
Small interfering RNA (siRNA) is an effective and specific method for silencing genes. However, an efficient and non-toxic carrier is needed to deliver the siRNA into the target cells. Tumor necrosis factor α (TNF-α) plays a central role in the occurrence and progression of rheumatoid arthritis (RA). In this study, we pre-synthetized a degradable cationic polymer (PDAPEI) from 2,6-pyridinedicarboxaldehyde and low-molecular-weight polyethyleneimine (PEI, Mw = 1.8 kDa) as a gene vector for the delivery of TNF-α shRNA...
2016: Frontiers in Immunology
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