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Mark A DeWitt, Wendy Magis, Nicolas L Bray, Tianjiao Wang, Jennifer R Berman, Fabrizia Urbinati, Seok-Jin Heo, Therese Mitros, Denise P Muñoz, Dario Boffelli, Donald B Kohn, Mark C Walters, Dana Carroll, David I K Martin, Jacob E Corn
Genetic diseases of blood cells are prime candidates for treatment through ex vivo gene editing of CD34(+) hematopoietic stem/progenitor cells (HSPCs), and a variety of technologies have been proposed to treat these disorders. Sickle cell disease (SCD) is a recessive genetic disorder caused by a single-nucleotide polymorphism in the β-globin gene (HBB). Sickle hemoglobin damages erythrocytes, causing vasoocclusion, severe pain, progressive organ damage, and premature death. We optimize design and delivery parameters of a ribonucleoprotein (RNP) complex comprising Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor (ssODN), to enable efficient replacement of the SCD mutation in human HSPCs...
October 12, 2016: Science Translational Medicine
Maria D Molina-Sánchez, Fernando M García-Rodríguez, Nicolás Toro
The functional unit of mobile group II introns is a ribonucleoprotein particle (RNP) consisting of the intron-encoded protein (IEP) and the excised intron RNA. The IEP has reverse transcriptase activity but also promotes RNA splicing, and the RNA-protein complex triggers site-specific DNA insertion by reverse splicing, in a process called retrohoming. In vitro reconstituted ribonucleoprotein complexes from the Lactococcus lactis group II intron Ll.LtrB, which produce a double strand break, have recently been studied as a means of developing group II intron-based gene targeting methods for higher organisms...
2016: Frontiers in Molecular Biosciences
Lizna M Ali, Tahir A Rizvi, Farah Mustafa
Retroviruses belong to the family Retroviridae and are ribonucleoprotein (RNP) particles that contain a dimeric RNA genome. Retroviral particle assembly is a complex process, and how the virus is able to recognize and specifically capture the genomic RNA (gRNA) among millions of other cellular and spliced retroviral RNAs has been the subject of extensive investigation over the last two decades. The specificity towards RNA packaging requires higher order interactions of the retroviral gRNA with the structural Gag proteins...
October 11, 2016: Viruses
Indulekha P Sudhakaran, Mani Ramaswami
Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives...
October 11, 2016: RNA Biology
Amandine Ketele, Tamás Kiss, Beáta E Jády
Mammalian cells express hundreds of intron-encoded box H/ACA RNAs which fold into a common hairpin-hinge-hairpin-tail structure, interact with four evolutionarily conserved proteins, dyskerin, Nop10, Nhp2 and Gar1, and function mainly in RNA pseudouridylation. The human telomerase H/ACA RNA (hTR) directs telomeric DNA synthesis and it carries a 5'-terminal domain encompassing the telomeric template sequence. The primary hTR transcript is synthesized from an independent gene by RNA polymerase II and undergoes 3' end processing controlled by the 3'-terminal H/ACA domain...
October 11, 2016: RNA Biology
Rajendra Kumar Agrawal, Hong-Wei Wang, Marlene Belfort
Group II introns are large catalytic RNAs that form a ribonucleoprotein (RNP) complex by binding to an intron-encoded protein (IEP). The IEP, which facilitates both RNA splicing and intron mobility, has multiple activities including reverse transcriptase. Recent structures of a group II intron RNP complex and of IEPs from diverse bacteria fuel arguments that group II introns are ancestrally related to eukaryotic spliceosomes as well as to telomerase and viruses. Furthermore, recent structural studies of various functional states of the spliceosome allow us to draw parallels between the group II intron RNP and the spliceosome...
October 11, 2016: RNA Biology
Andrew J Love, Chulang Yu, Natalia V Petukhova, Natalia O Kalinina, Jianping Chen, Michael E Taliansky
Cajal bodies (CBs) are distinct sub-nuclear structures that are present in eukaryotic living cells and are often associated with the nucleolus. CBs play important roles in RNA metabolism and formation of RNPs involved in transcription, splicing, ribosome biogenesis, and telomere maintenance. Besides these primary roles, CBs appear to be involved in additional functions that may not be directly related to RNA metabolism and RNP biogenesis. In this review, we assess possible roles of plant CBs in RNA regulatory pathways such as nonsense-mediated mRNA decay and RNA silencing...
October 11, 2016: RNA Biology
Michael D Hebert, Aaron R Poole
The biogenesis of small nuclear ribonucleoproteins (snRNPs), small Cajal body-specific RNPs (scaRNPs), small nucleolar RNPs (snoRNPs) and the telomerase RNP involves Cajal bodies (CBs). Although many components enriched in the CB contain post-translational modifications (PTMs), little is known about how these modifications impact individual protein function within the CB and, in concert with other modified factors, collectively regulate CB activity. Since all components of the CB also reside in other cellular locations, it is also important that we understand how PTMs affect the subcellular localization of CB components...
October 7, 2016: RNA Biology
Séverine Massenet, Edouard Bertrand, Céline Verheggen
Box C/D and box H/ACA snoRNAs are abundant non-coding RNAs that localize in the nucleolus and mostly function as guides for nucleotide modifications. While a large pool of snoRNAs modifies ribosomal RNAs, an increasing number of snoRNAs could also potentially target mRNAs. ScaRNAs belong to a family of specific RNAs that localize in Cajal bodies and that are structurally similar to snoRNAs. Most scaRNAs are involved in snRNA modification, while telomerase RNA, which contains H/ACA motifs, functions in telomeric DNA synthesis...
October 7, 2016: RNA Biology
Chih-Hao Chang, Fu-Chen Hsu, Shu-Chuan Lee, Yih-Shan Lo, Jiun-Da Wang, Jane Shaw, Michael Taliansky, Ban-Yang Chang, Yau-Heiu Hsu, Na-Sheng Lin
RNA trafficking plays pivotal roles in regulating plant development, gene silencing, and adaptation to environmental stress. Satellite RNAs (satRNAs), parasites of viruses, depend on their helper viruses (HVs) for replication, encapsidation, and efficient spread. However, it remains largely unknown how satRNAs interact with viruses and the cellular machinery to undergo trafficking. Here, we show that the P20 protein of Bamboo mosaic potexvirus satRNA (satBaMV) can functionally complement in trans the systemic trafficking of P20-defective satBaMV in infected Nicotiana benthamiana...
October 4, 2016: Plant Cell
M N Drehmer, D Andrade, I A Pereira, A R Marrero, Y C N Muniz, I R de Souza, S E Löfgren
BACKGROUND: Estrogens have a modulatory effect on several immune responses, many of which are correlated to autoimmune diseases. Estrogens act through binding to their receptors, and an overexpression of these receptors has been identified in patients with different autoimmune diseases. Here we analyzed the association of a putative functional genetic variant in the main estrogen receptor (ERα) gene (ESR1), and the susceptibility to clinical findings and severity of SLE. METHODS: A total of 426 individuals (266 healthy controls and 160 SLE patients) were genotyped for the polymorphism rs2234693 in the ESR1 gene...
September 27, 2016: Lupus
James Kirui, Arindam Mondal, Andrew Mehle
: The influenza A virus polymerase plays an essential role in the virus lifecycle, directing synthesis of viral mRNAs and genomes. It is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher order ribonucleoprotein (RNP) complexes. The polymerase is regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including post-translational modifications, however the mechanisms are not fully understood...
September 28, 2016: Journal of Virology
Xiaojing Wang, Baobin Li, Yu Guo, Shu Shen, Liang Zhao, Peisheng Zhang, Yuna Sun, Sen-Fang Sui, Fei Deng, Zhiyong Lou
Negative-sense single-strand RNA (-ssRNA) viruses comprise a large family of pathogens that cause severe human infectious diseases. All -ssRNA viruses encode a nucleocapsid protein (NP) to encapsidate the viral genome, which, together with polymerase, forms a ribonucleoprotein complex (RNP) that is packaged into virions and acts as the template for viral replication and transcription. In our previous work, we solved the monomeric structure of NP encoded by Crimean-Congo hemorrhagic fever virus (CCHFV), which belongs to the Nairovirus genus within the Bunyaviridae family, and revealed its unusual endonuclease activity...
September 22, 2016: Journal of Structural Biology
Laura Trinkle-Mulcahy, Judith E Sleeman
From their initial identification as 'nucleolar accessory bodies' more than a century ago, the relationship between Cajal bodies and nucleoli has been a subject of interest and controversy. In this review, we seek to place recent developments in the understanding of the physical and functional relationships between the two structures in the context of historical observations. Biophysical models of nuclear body formation, the molecular nature of CB/nucleolus interactions and the increasing list of joint roles for CBs and nucleoli, predominantly in assembling ribonucleoprotein (RNP) complexes, are discussed...
September 23, 2016: RNA Biology
Elisa Orecchini, Margherita Doria, Ambra Antonioni, Silvia Galardi, Silvia Anna Ciafrè, Loredana Frassinelli, Carmine Mancone, Claudia Montaldo, Marco Tripodi, Alessandro Michienzi
Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosines to inosines in double-stranded RNAs. ADAR1 was demonstrated to be functional on different viruses exerting either antiviral or proviral effects. Concerning HIV-1, several studies showed that ADAR1 favors viral replication. The aim of this study was to investigate the composition of the ADAR1 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 14 non-ribosomal ADAR1-interacting proteins, most of which are novel...
September 21, 2016: Nucleic Acids Research
Amanda C Raimer, Kelsey M Gray, A Gregory Matera
Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation...
September 20, 2016: RNA Biology
Olga Reifschneider, Christina Marx, Jessica Jacobs, Laxmikanth Kollipara, Albert Sickmann, Dirk Wolters, Ulrich Kück
In the chloroplast of the green alga Chlamydomonas reinhardtii, two discontinuous group II introns, psaA-i1 and psaA-i2, splice in trans and thus their excision process resembles the nuclear spliceosomal splicing pathway. Here, we address the question whether fragmentation of trans-acting RNAs is accompanied by the formation of a chloroplast spliceosome-like machinery. Using a combination of liquid chromatography-mass spectrometry (LC-MS), size exclusion chromatography (SEC), and quantitative RT-PCR, we provide the first characterization of a high molecular weight ribonucleoprotein (RNP) apparatus participating in psaA mRNA splicing...
September 19, 2016: Journal of Biological Chemistry
Zuxiao Yang, Jinzhong Lin, Keqiong Ye
Box C/D RNAs guide site-specific 2'-O-methylation of RNAs in archaea and eukaryotes. The spacer regions between boxes C to D' and boxes C' to D contain the guide sequence that can form a stretch of base pairs with substrate RNAs. The lengths of spacer regions and guide-substrate duplexes are variable among C/D RNAs. In a previously determined structure of C/D ribonucleoprotein (RNP), a 12-nt-long spacer forms 10 bp with the substrate. How spacers and guide-substrate duplexes of other lengths are accommodated remains unknown...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Vrutant V Shah, Benjamin Soibam, Ruth A Ritter, Ashley Benham, Jamina Oomen, Amy K Sater
The establishment of cell lineages occurs via a dynamic progression of gene regulatory networks (GRNs) that underlie developmental commitment and differentiation. To investigate how microRNAs (miRs) function in this process, we compared miRs and miR targets at the initiation of the two major ectodermal lineages in Xenopus. We used next-generation sequencing to identify over 170 miRs expressed in midgastrula ectoderm expressing either noggin or a constitutively active BMP receptor, reflecting anterior neural or epidermal ectoderm, respectively; 125 had not previously been identified in Xenopus...
September 10, 2016: Developmental Biology
Nancy A Stearns, Shuxia Zhou, Michelle Petri, Steven R Binder, David S Pisetsky
Antibodies to nuclear antigens (antinuclear antibodies or ANAs) are the serological hallmark of systemic lupus erythematosus (SLE). These antibodies bind diverse nuclear antigens that include DNA, histones and non-histone proteins as well as complexes of proteins with DNA and RNA. Because of the frequency of ANA expression in SLE, testing is an important component of clinical evaluation as well as determination of eligibility for clinical trials or utilization of certain therapies. Immunofluorescence assays have been commonly used for this purpose although this approach can be limited by issues of throughput, variability and difficulty in determining positivity...
2016: PloS One
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