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https://www.readbyqxmd.com/read/29160308/programmable-base-editing-of-a%C3%A2-t-to-g%C3%A2-c-in-genomic-dna-without-dna-cleavage
#1
Nicole M Gaudelli, Alexis C Komor, Holly A Rees, Michael S Packer, Ahmed H Badran, David I Bryson, David R Liu
The spontaneous deamination of cytosine is a major source of C•G to T•A transitions, which account for half of known human pathogenic point mutations. The ability to efficiently convert target A•T base pairs to G•C could therefore advance the study and treatment of genetic diseases. While the deamination of adenine yields inosine, which is treated as guanine by polymerases, no enzymes are known to deaminate adenine in DNA. Here we report adenine base editors (ABEs) that mediate conversion of A•T to G•C in genomic DNA...
October 25, 2017: Nature
https://www.readbyqxmd.com/read/29146145/adars-and-editing-the-role-of-a-to-i-rna-modification-in-cancer-progression
#2
REVIEW
Kajsa Fritzell, Li-Di Xu, Jens Lagergren, Marie Öhman
Cancer arises when pathways that control cell functions such as proliferation and migration are dysregulated to such an extent that cells start to divide uncontrollably and eventually spread throughout the body, ultimately endangering the survival of an affected individual. It is well established that somatic mutations are important in cancer initiation and progression as well as in creation of tumor diversity. Now also modifications of the transcriptome are emerging as a significant force during the transition from normal cell to malignant tumor...
November 16, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29145975/in-cancer-a-to-i-rna-editing-can-be-the-driver-the-passenger-or-the-mechanic
#3
Nabeel S Ganem, Noa Ben-Asher, Ayelet T Lamm
In recent years, A-to-I RNA modifications performed by the Adenosine Deaminase Acting on RNA (ADAR) protein family were found to be expressed at altered levels in multiple human malignancies. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, thereby changing transcript sequence and structure. Although A-to-I RNA editing have the potential to change essential mRNA transcripts, affecting their corresponding protein structures, most of the human editing sites identified to date reside in non-coding repetitive transcripts such as Alu elements...
May 2017: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/29132308/effect-of-two-non-synonymous-ecto-5-nucleotidase-variants-on-the-genetic-architecture-of-inosine-5-monophosphate-imp-and-its-degradation-products-in-japanese-black-beef
#4
Yoshinobu Uemoto, Tsuyoshi Ohtake, Nanae Sasago, Masayuki Takeda, Tsuyoshi Abe, Hironori Sakuma, Takatoshi Kojima, Shinji Sasaki
BACKGROUND: Umami is a Japanese term for the fifth basic taste and is an important sensory property of beef palatability. Inosine 5'-monophosphate (IMP) contributes to umami taste in beef. Thus, the overall change in concentration of IMP and its degradation products can potentially affect the beef palatability. In this study, we investigated the genetic architecture of IMP and its degradation products in Japanese Black beef. First, we performed genome-wide association study (GWAS), candidate gene analysis, and functional analysis to detect the causal variants that affect IMP, inosine, and hypoxanthine...
November 13, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29129909/rna-editing-by-adar1-leads-to-context-dependent-transcriptome-wide-changes-in-rna-secondary-structure
#5
Oz Solomon, Ayelet Di Segni, Karen Cesarkas, Hagit T Porath, Victoria Marcu-Malina, Orel Mizrahi, Noam Stern-Ginossar, Nitzan Kol, Sarit Farage-Barhom, Efrat Glick-Saar, Yaniv Lerenthal, Erez Y Levanon, Ninette Amariglio, Ron Unger, Itamar Goldstein, Eran Eyal, Gidi Rechavi
Adenosine deaminase acting on RNA 1 (ADAR1) is the master RNA editor, catalyzing the deamination of adenosine to inosine. RNA editing is vital for preventing abnormal activation of cytosolic nucleic acid sensing pathways by self-double-stranded RNAs. Here we determine, by parallel analysis of RNA secondary structure sequencing (PARS-seq), the global RNA secondary structure changes in ADAR1 deficient cells. Surprisingly, ADAR1 silencing resulted in a lower global double-stranded to single-stranded RNA ratio, suggesting that A-to-I editing can stabilize a large subset of imperfect RNA duplexes...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29127844/the-role-of-a-to-i-rna-editing-in-cancer-development
#6
REVIEW
Xiaoyan Xu, Yumeng Wang, Han Liang
Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post-transcriptional nucleotide modification in humans, which is catalyzed in ADAR enzymes. Recent genomic studies have revealed thousands of altered RNA editing events in various cancer tissues, leading to diverse functional consequences. A critical role of individual A-to-I RNA editing events in cancer has been reported. Here, we review the current state of our knowledge on key A-to-I RNA editing events in coding and non-coding regions for their roles in cancer development and discuss their potential clinical utility...
November 8, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/29127211/mechanistic-implications-of-enhanced-editing-by-a-hypertribe-rna-binding-protein
#7
Weijin Xu, Reazur Rahman, Michael Rosbash
We previously developed TRIBE, a method for the identification of cell-specific RNA binding protein targets. TRIBE expresses an RBP of interest fused to the catalytic domain (cd) of the RNA editing enzyme ADAR and performs Adenosine-to-Inosine editing on RNA targets of the RBP. However, target identification is limited by the low editing efficiency of the ADARcd. Here we describe HyperTRIBE, which carries a previously characterized hyperactive mutation (E488Q) of the ADARcd. HyperTRIBE identifies dramatically more editing sites, many of which are also edited by TRIBE but at a much lower editing frequency...
November 10, 2017: RNA
https://www.readbyqxmd.com/read/29126977/enhancement-of-inosine-mediated-a2ar-signaling-through-positive-allosteric-modulation
#8
Ajith A Welihinda, Manmeet Kaur, Kaviya S Raveendran, Edward P Amento
Inosine is an endogenous nucleoside that is produced by metabolic deamination of adenosine. Inosine is metabolically more stable (half-life 15h) than adenosine (half-life <10s). Inosine exerts anti-inflammatory and immunomodulatory effects similar to those observed with adenosine. These effects are mediated in part through the adenosine A2A receptor (A2AR). Relative to adenosine inosine exhibits a lower affinity towards the A2AR. Therefore, it is generally believed that inosine is incapable of activating the A2AR through direct engagement, but indirectly activates the A2AR upon metabolic conversion to higher affinity adenosine...
November 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29126899/merimepodib-an-impdh-inhibitor-suppresses-replication-of-zika-virus-and-other-emerging-viral-pathogens
#9
Xiao Tong, Jeanon Smith, Natalya Bukreyeva, Takaaki Koma, John T Manning, Raj Kalkeri, Ann D Kwong, Slobodan Paessler
Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to abnormal pregnancies, fetal death, microcephaly, and Guillain-Barré syndrome in humans. Merimepodib (MMPD, VX-497), a potent inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), has shown antiviral activity against HCV and a variety of DNA and RNA viruses in vitro. In this report, we expand the antiviral spectrum of MMPD, and demonstrate that MMPD inhibits ZIKV RNA replication with an EC50 of 0.6 μM. Furthermore, MMPD reduces the virus production of ZIKV as well as several other important emerging viral pathogens such as Ebola, Lassa, Chikungunya, and Junin viruses...
November 8, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29124970/a-review-on-the-nucleic-acid-constituents-in-mushrooms-nucleobases-nucleosides-and-nucleotides
#10
Chia-Wei Phan, Joon-Keong Wang, Shiau-Chuen Cheah, Murali Naidu, Pamela David, Vikineswary Sabaratnam
Mushrooms have become increasingly important as a reliable food source. They have also been recognized as an important source of bioactive compounds of high nutritional and medicinal values. The nucleobases, nucleosides and nucleotides found in mushrooms play important roles in the regulation of various physiological processes in the human body via the purinergic and/or pyrimidine receptors. Cordycepin, a 3'-deoxyadenosine found in Cordyceps sinensis has received much attention as it possesses many medicinal values including anticancer properties...
November 10, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/29120945/a-comparison-of-red-cell-rejuvenation-versus-mechanical-washing-for-the-prevention-of-transfusion-associated-organ-injury-in-swine
#11
Marcin J Woźniak, Saqib Qureshi, Nikol Sullo, William Dott, Rebecca Cardigan, Michael Wiltshire, Mintu Nath, Nishith N Patel, Tracy Kumar, Alison H Goodall, Gavin J Murphy
BACKGROUND: We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. METHODS: White-landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device...
November 9, 2017: Anesthesiology
https://www.readbyqxmd.com/read/29113319/comparative-proteomic-analysis-of-virulent-and-avirulent-strains-of-toxoplasma-gondii-reveals-strain-specific-patterns
#12
Dong-Hui Zhou, Ze-Xiang Wang, Chun-Xue Zhou, Shuai He, Hany M Elsheikha, Xing-Quan Zhu
Research exploring the proteome of Toxoplasma gondii oocysts has gained momentum over the past few years. However, little is known about the oocyst's protein repertoires that contribute to differential virulence among T. gondii strains. Here, we used isobaric tag for relative and absolute quantitation-based proteomic analysis of oocysts of two T. gondii strains exhibiting the virulent PYS (ToxoDB#9) phenotype versus the less virulent PRU (Type II, ToxoDB#1) phenotype. Our aim was to determine protein expression patterns that contribute to the virulence of a particular phenotype...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29109710/aedes-aegypti-molecular-responses-to-zika-virus-modulation-of-infection-by-the-toll-and-jak-stat-immune-pathways-and-virus-host-factors
#13
Yesseinia I Angleró-Rodríguez, Hannah J MacLeod, Seokyoung Kang, Jenny S Carlson, Natapong Jupatanakul, George Dimopoulos
Zika (ZIKV) and dengue virus (DENV) are transmitted to humans by Aedes mosquitoes. However, the molecular interactions between the vector and ZIKV remain largely unexplored. In this work, we further investigated the tropism of ZIKV in two different Aedes aegypti strains and show that the virus infection kinetics, tissue migration, and susceptibility to infection differ between mosquito strains. We also compare the vector transcriptome changes upon ZIKV or DENV infection demonstrating that 40% of the mosquito's midgut infection-responsive transcriptome is virus-specific at 7 days after virus ingestion...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29099293/abundant-off-target-edits-from-site-directed-rna-editing-can-be-reduced-by-nuclear-localization-of-the-editing-enzyme
#14
Isabel C Vallecillo-Viejo, Noa Liscovitch-Brauer, Maria Fernanda Montiel-Gonzalez, Eli Eisenberg, Joshua J C Rosenthal
Site-directed RNA editing (SDRE) is a general strategy for making targeted base changes in RNA molecules. Although the approach is relatively new, several groups, including our own, have been working on its development. The basic strategy has been to couple the catalytic domain of an adenosine (A) to inosine (I) RNA editing enzyme to a guide RNA that is used for targeting. Although highly efficient on-target editing has been reported, off-target events have not been rigorously quantified. In this report we target premature termination codons (PTCs) in messages encoding both a fluorescent reporter protein and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein transiently transfected into human epithelial cells...
November 3, 2017: RNA Biology
https://www.readbyqxmd.com/read/29090729/tricyclanos-conformationally-constrained-nucleoside-analogues-with-a-new-heterotricycle-obtained-from-a-d-ribofuranose-unit
#15
Máté Kicsák, Attila Mándi, Szabolcs Varga, Mihály Herczeg, Gyula Batta, Attila Bényei, Anikó Borbás, Pál Herczegh
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.0(5,11)]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity...
November 1, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29090559/-liver-metabonomics-of-acute-gouty-arthritis-treated-by-diosocorea-nipponica
#16
Shu-Min Liu, Ning Zhang, Dong-Hua Yu, Yu Wang, Qi Zhou, Fang Lu
To explore the prevention and protection effect of Diosocorea nipponica (DNM)) on acute gouty arthritis (AGA) rats based on liver metabonomics, and find potential biomarkers and related pathways. AGA model rats were induced by monosodium urate crystal suspension. UPLC-TOF-MS coupled with pattern recognition technique was employed to find out the potential biomarkers and related metabolic pathways. Eleven common potential biomarkers were identified. Among the potential intervention targets in normal rats given by DNM, 4 biomarkers were up-regulated, and the other 4 targets were down regulated...
May 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29084235/biophysical-and-functional-characterization-of-the-n-terminal-domain-of-the-cat-t1r1-umami-taste-receptor-expressed-in-escherichia-coli
#17
Christine Belloir, Jimmy Savistchenko, Fabrice Neiers, Andrew J Taylor, Scott McGrane, Loïc Briand
Umami taste perception is mediated by the heterodimeric G-protein coupled receptors (GPCRs), formed by the assembly of T1R1 and T1R3 subunits. T1R1 and T1R3 subunits are class C GPCRs whose members share common structural homologies including a long N-terminal domain (NTD) linked to a seven transmembrane domain by a short cysteine-rich region. The NTD of the T1R1 subunit contains the primary binding site for umami stimuli, such as L-glutamate (L-Glu) for humans. Inosine-5'-monophosphate (IMP) binds at a location close to the opening of the T1R1-NTD "flytrap", thus creating the observed synergistic response between L-Glu and IMP...
2017: PloS One
https://www.readbyqxmd.com/read/29078406/site-directed-rna-repair-of-endogenous-mecp2-rna-in-neurons
#18
John R Sinnamon, Susan Y Kim, Glen M Corson, Zhen Song, Hiroyuki Nakai, John P Adelman, Gail Mandel
Rett syndrome (RTT) is a debilitating neurological disorder caused by mutations in the gene encoding the transcription factor Methyl CpG Binding Protein 2 (MECP2). A distinct disorder results from MECP2 gene duplication, suggesting that therapeutic approaches must restore close to normal levels of MECP2. Here, we apply the approach of site-directed RNA editing to repair, at the mRNA level, a disease-causing guanosine to adenosine (G > A) mutation in the mouse MeCP2 DNA binding domain. To mediate repair, we exploit the catalytic domain of Adenosine Deaminase Acting on RNA (ADAR2) that deaminates A to inosine (I) residues that are subsequently translated as G...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29070703/rna-editing-with-crispr-cas13
#19
David B T Cox, Jonathan S Gootenberg, Omar O Abudayyeh, Brian Franklin, Max J Kellner, Julia Joung, Feng Zhang
Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI CRISPR-Cas systems contain the programmable single-effector RNA-guided RNases Cas13. Here, we profile Type VI systems to engineer a Cas13 ortholog capable of robust knockdown and demonstrate RNA editing by using catalytically-inactive Cas13 (dCas13) to direct adenosine to inosine deaminase activity by ADAR2 to transcripts in mammalian cells...
October 25, 2017: Science
https://www.readbyqxmd.com/read/29063699/characterization-of-aicar-transformylase-imp-cyclohydrolase-atic-from-staphylococcus-lugdunensis
#20
Preeti Verma, Bibekananda Kar, Ritu Varshney, Partha Roy, Ashwani K Sharma
The 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/inosine monophosphate (IMP) cyclohydrolase (ATIC) catalyzes final two steps of purine nucleotide de novo biosynthetic pathway. The present study reports the characterization of ATIC from Staphylococcus lugdunensis (SlugATIC). Apart from kinetic analysis and a detailed biophysical characterization of SlugATIC, the role of ATIC in cell proliferation has been demonstrated for the first time. The purified recombinant SlugATIC and its truncated domains exists mainly in dimeric form was revealed in gel filtration and glutaraldehyde cross linking studies...
October 24, 2017: FEBS Journal
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