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Anti crispr

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https://www.readbyqxmd.com/read/28706995/disabling-cas9-by-an-anti-crispr-dna-mimic
#1
Jiyung Shin, Fuguo Jiang, Jun-Jie Liu, Nicolas L Bray, Benjamin J Rauch, Seung Hyun Baik, Eva Nogales, Joseph Bondy-Denomy, Jacob E Corn, Jennifer A Doudna
CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 gene editing technology is derived from a microbial adaptive immune system, where bacteriophages are often the intended target. Natural inhibitors of CRISPR-Cas9 enable phages to evade immunity and show promise in controlling Cas9-mediated gene editing in human cells. However, the mechanism of CRISPR-Cas9 inhibition is not known, and the potential applications for Cas9 inhibitor proteins in mammalian cells have not been fully established...
July 2017: Science Advances
https://www.readbyqxmd.com/read/28705213/the-therapeutic-landscape-of-hiv-1-via-genome-editing
#2
REVIEW
Alexander Kwarteng, Samuel Terkper Ahuno, Godwin Kwakye-Nuako
Current treatment for HIV-1 largely relies on chemotherapy through the administration of antiretroviral drugs. While the search for anti-HIV-1 vaccine remain elusive, the use of highly active antiretroviral therapies (HAART) have been far-reaching and has changed HIV-1 into a manageable chronic infection. There is compelling evidence, including several side-effects of ARTs, suggesting that eradication of HIV-1 cannot depend solely on antiretrovirals. Gene therapy, an expanding treatment strategy, using RNA interference (RNAi) and programmable nucleases such as meganuclease, zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins (CRISPR-Cas9) are transforming the therapeutic landscape of HIV-1...
July 14, 2017: AIDS Research and Therapy
https://www.readbyqxmd.com/read/28668720/inhibition-of-crispr-cas-systems-by-mobile-genetic-elements
#3
REVIEW
Erik J Sontheimer, Alan R Davidson
Clustered, regularly interspaced, short, palindromic repeats (CRISPR) loci, together with their CRISPR-associated (Cas) proteins, provide bacteria and archaea with adaptive immunity against invasion by bacteriophages, plasmids, and other mobile genetic elements. These host defenses impart selective pressure on phages and mobile elements to evolve countermeasures against CRISPR immunity. As a consequence of this pressure, phages and mobile elements have evolved 'anti-CRISPR' proteins that function as direct inhibitors of diverse CRISPR-Cas effector complexes...
June 29, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/28667332/viperin-is-an-important-host-restriction-factor-in-control-of-zika-virus-infection
#4
Kylie H Van der Hoek, Nicholas S Eyre, Byron Shue, Onruedee Khantisitthiporn, Kittirat Glab-Ampi, Jillian M Carr, Matthew J Gartner, Lachlan A Jolly, Paul Q Thomas, Fatwa Adikusuma, Tanja Jankovic-Karasoulos, Claire T Roberts, Karla J Helbig, Michael R Beard
Zika virus (ZIKV) infection has emerged as a global health threat and infection of pregnant women causes intrauterine growth restriction, spontaneous abortion and microcephaly in newborns. Here we show using biologically relevant cells of neural and placental origin that following ZIKV infection, there is attenuation of the cellular innate response characterised by reduced expression of IFN-β and associated interferon stimulated genes (ISGs). One such ISG is viperin that has well documented antiviral activity against a wide range of viruses...
June 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28663543/nr3c1-null-mutant-zebrafish-are-viable-and-reveal-dna-binding-independent-activities-of-the-glucocorticoid-receptor
#5
N Facchinello, T Skobo, G Meneghetti, E Colletti, A Dinarello, N Tiso, R Costa, G Gioacchini, O Carnevali, F Argenton, L Colombo, L Dalla Valle
Glucocorticoids (GCs) play important roles in developmental and physiological processes through the transcriptional activity of their cognate receptor (Gr). Using CRISPR/Cas9 technology, we established a zebrafish null Gr mutant line and compared its phenotypes with wild type and a zebrafish line with partially silenced gr (gr (s357/s357) ). Homozygous gr (-/-) larvae are morphologically inconspicuous and, in contrast to GR (-/-) knockout mice, viable through adulthood, although with reduced fitness and early life survival...
June 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28656178/gene-knockout-shows-that-pml-trim19-does-not-restrict-the-early-stages-of-hiv-1-infection-in-human-cell-lines
#6
Nasser Masroori, Pearl Cherry, Natacha Merindol, Jia-Xin Li, Caroline Dufour, Lina Poulain, Mélodie B Plourde, Lionel Berthoux
The PML (promyelocytic leukemia) protein is a member of the TRIM family, a large group of proteins that show high diversity in functions but possess a common tripartite motif giving the family its name. We and others recently reported that both murine PML (mPML) and human PML (hPML) strongly restrict the early stages of infection by HIV-1 and other lentiviruses when expressed in mouse embryonic fibroblasts (MEFs). This restriction activity was found to contribute to the type I interferon (IFN-I)-mediated inhibition of HIV-1 in MEFs...
May 2017: MSphere
https://www.readbyqxmd.com/read/28628795/knockout-of-the-nogo-b-gene-attenuates-tumor-growth-and-metastasis-in-hepatocellular-carcinoma
#7
Bo Zhu, Shaobo Chen, Xiaoding Hu, Xiaofeng Jin, Yichen Le, Lihuan Cao, Zhonghua Yuan, Zhen Lin, Songmin Jiang, Lichun Sun, Long Yu
Human hepatocellular carcinoma (HCC) is a malignant cancer. It is a challenge to develop anti-HCC drugs due to HCC's extreme aggressiveness and with the sensitivity of the liver to show severe adverse effects. More importantly, the precise mechanisms causing HCC pathogenicity are not known. Our previous study disclosed Nogo-B as a reticulon 4 (Rtn4) family member. In the present study, we first identified that Nogo-B played a critical role in HCC progression. We found, via in vitro and in vivo assays, that Nogo-B was expressed aberrantly in primary HCC tumor tissues and immortal HCC cells but was relatively scarce in the normal liver tissues or cells...
July 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28621109/comparative-genomic-analysis-of-lactobacillus-plantarum-gb-lp1-isolated-from-traditional-korean-fermented-food
#8
Jihyun Yu, Sojin Ahn, Kwondo Kim, Kelsey Caetano-Anolles, Chanho Lee, Jungsun Kang, Kyungjin Cho, SookHee Yoon, Dae-Kyung Kang, Heebal Kim
As probiotics play an important role in maintaining a healthy gut flora environment through antitoxin activity and inhibition of pathogen colonization, they have been of interest to the medical research community for quite some time now. Probiotic bacteria such as Lactobacillus plantarum, which can be found in fermented food, are of particular interest given their easy accessibility. We performed whole genome sequencing and genomic analysis on a GB-LP1 strain of L. plantarum isolated from Korean traditional fermented food; this strain is well known for its functions in immune response, suppression of pathogen growth and anti-toxin effects...
June 16, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28619709/loss-of-fam46c-promotes-cell-survival-in-myeloma
#9
Yuan Xiao Zhu, Chang-Xin Shi, Laura A Bruins, Patrick Jedlowski, Xuewei Wang, K Martin Kortüm, Moulun Luo, Jonathan Ahmann, Esteban Braggio, A Keith Stewart
FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis has not been determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response (UPR) pathway and induced mitochondrial dysfunction...
June 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28602637/inhibition-mechanism-of-an-anti-crispr-suppressor-acriia4-targeting-spycas9
#10
Hui Yang, Dinshaw J Patel
Prokaryotic CRISPR-Cas adaptive immune systems utilize sequence-specific RNA-guided endonucleases to defend against infection by viruses, bacteriophages, and mobile elements, while these foreign genetic elements evolve diverse anti-CRISPR proteins to overcome the CRISPR-Cas-mediated defense of the host. Recently, AcrIIA2 and AcrIIA4, encoded by Listeria monocytogene prophages, were shown to block the endonuclease activity of type II-A Streptococcus pyogene Cas9 (SpyCas9). We now report the crystal structure of AcrIIA4 in complex with single-guide RNA-bound SpyCas9, thereby establishing that AcrIIA4 preferentially targets critical residues essential for PAM duplex recognition, as well as blocks target DNA access to key catalytic residues lining the RuvC pocket...
July 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28574055/alternate-binding-modes-of-anti-crispr-viral-suppressors-acrf1-2-to-csy-surveillance-complex-revealed-by-cryo-em-structures
#11
Ruchao Peng, Ying Xu, Tengfei Zhu, Ningning Li, Jianxun Qi, Yan Chai, Min Wu, Xinzheng Zhang, Yi Shi, Peiyi Wang, Jiawei Wang, Ning Gao, George Fu Gao
Bacteriophages encode anti-CRISPR suppressors to counteract the CRISPR/Cas immunity of their bacterial hosts, thus facilitating their survival and replication. Previous studies have shown that two phage-encoded anti-CRISPR proteins, AcrF1 and AcrF2, suppress the type I-F CRISPR/Cas system of Pseudomonas aeruginosa by preventing target DNA recognition by the Csy surveillance complex, but the precise underlying mechanism was unknown. Here we present the structure of AcrF1/2 bound to the Csy complex determined by cryo-EM single-particle reconstruction...
July 2017: Cell Research
https://www.readbyqxmd.com/read/28572528/apex2-enhanced-electron-microscopy-distinguishes-sigma-1-receptor-localization-in-the-nucleoplasmic-reticulum
#12
Timur A Mavlyutov, Huan Yang, Miles L Epstein, Arnold E Ruoho, Jay Yang, Lian-Wang Guo
The sigma-1 receptor (Sig1R) is an endoplasmic reticulum chaperonin that is attracting tremendous interest as a potential anti-neurodegenerative target. While this membrane protein is known to reside in the inner nuclear envelope (NE) and influences transcription, apparent Sig1R presence in the nucleoplasm is often observed, seemingly contradicting its NE localization. We addressed this confounding issue by applying an antibody-free approach of electron microscopy (EM) to define Sig1R nuclear localization. We expressed APEX2 peroxidase fused to Sig1R-GFP in a Sig1R-null NSC34 neuronal cell line generated with CRISPR-Cas9...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28535607/generation-of-the-new-discovered-resistant-gene-mcr-1-knockout-in-escherichia-coli-using-crispr-cas9-system
#13
Lichang Sun, Tao He, Lili Zhang, Maoda Pang, Qiaoyan Zhang, Yan Zhou, Hongduo Bao, Ran Wang
The mcr-1 gene was the new discovered "superbug" gene which makes the bacteria highly resistant to the last-resort class of antibiotics in China in 2016. The mcr-1 gene raised serious concern about its possible global dissemination and spread. Here, we report a potential anti-resistant strategy that CRISPR/Cas9 mediated approach can efficiently induce mcr-1 gene knockout in Escherichia coli. Our findings suggested that using CRISPPR/Cas9 system to knockout the resistant gene mcr-1 might be a potential anti-resistant strategy...
May 24, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28487966/oligomeric-proanthocyanidins-protects-a549-cells-against-h2o2-induced-oxidative-stress-via-the-nrf2-are-pathway
#14
Chao Sun, Weiguo Jin, Hongcan Shi
Oxidative signaling and oxidative stress contribute to aging, cancer and diseases resulting from lung fibrosis. In this study, we explored the anti-oxidative potential of oligomeric proanthocyanidins (OPCs), natural flavonoid compounds. We examined the protective effects of OPCs against hydrogen peroxide (H2O2)-induced oxidative stress in non-small cell lung cancer cells (A549). We demonstrated that OPC markedly attenuated H2O2-induced A549 cell viability, as shown by by 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyl-tetrazolium bromide (MTT) assay...
June 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28475125/melatonin-promotes-the-in-vitro-development-of-microinjected-pronuclear-mouse-embryos-via-its-anti-oxidative-and-anti-apoptotic-effects
#15
Xiuzhi Tian, Feng Wang, Lu Zhang, Pengyun Ji, Jing Wang, Dongying Lv, Guangdong Li, Menglong Chai, Zhengxing Lian, Guoshi Liu
CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats) combined with pronuclear microinjection has become the most effective method for producing transgenic animals. However, the relatively low embryo developmental rate limits its application. In the current study, it was observed that 10(-7) M melatonin is considered an optimum concentration and significantly promoted the in vitro development of murine microinjected pronuclear embryos, as indicated by the increased blastocyst rate, hatching blastocyst rate and blastocyst cell number...
May 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28468826/neuropilin-1-mediates-neutrophil-elastase-uptake-and-cross-presentation-in-breast-cancer-cells
#16
Celine Kerros, Satyendra C Tripathi, Dongxing Zha, Jennifer M Mehrens, Anna Sergeeva, Anne V Philips, Na Qiao, Haley L Peters, Hiroyuki Katayama, Pariya Sukhumalchandra, Kathryn E Ruisaard, Alexander A Perakis, Lisa S St John, Sijie Lu, Elizabeth A Mittendorf, Karen Clise-Dwyer, Amanda C Herrmann, Gheath Alatrash, Carlo Toniatti, Samir M Hanash, Qing Ma, Jeffrey J Molldrem
Neutrophil elastase (NE) can be rapidly taken up by tumor cells that lack endogenous NE expression, including breast cancer, which results in cross-presentation of PR1, an NE-derived HLA-A2-restricted peptide that is an immunotherapy target in hematological and solid tumor malignancies. The mechanism of NE uptake, however, remains unknown. Using the mass spectrometry-based approach, we identify neuropilin-1 (NRP1) as a NE receptor that mediates uptake and PR1 cross-presentation in breast cancer cells. We demonstrated that soluble NE is a specific, high-affinity ligand for NRP1 with a calculated Kd of 38...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28457885/genome-engineering-of-stem-cells-for-autonomously-regulated-closed-loop-delivery-of-biologic-drugs
#17
Jonathan M Brunger, Ananya Zutshi, Vincent P Willard, Charles A Gersbach, Farshid Guilak
Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner...
May 9, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28456574/suppression-of-epstein-barr-virus-dna-load-in-latently-infected-nasopharyngeal-carcinoma-cells-by-crispr-cas9
#18
Kit-San Yuen, Zhong-Min Wang, Nok-Hei Mickey Wong, Zhi-Qian Zhang, Tsz-Fung Cheng, Wai-Yin Lui, Chi-Ping Chan, Dong-Yan Jin
Epstein-Barr virus (EBV) infects more than 90% of the world's adult population. Once established, latent infection of nasopharyngeal epithelial cells with EBV is difficult to eradicate and might lead to the development of nasopharyngeal carcinoma (NPC) in a small subset of individuals. In this study we explored the anti-EBV potential of CRISPR/Cas9 targeting of EBV genome in infected NPC cells. We designed gRNAs to target different regions of the EBV genome and transfected them into C666-1 cells. The levels of EBV DNA in transfected cells were decreased by about 50%...
April 27, 2017: Virus Research
https://www.readbyqxmd.com/read/28448066/structural-basis-of-crispr-spycas9-inhibition-by-an-anti-crispr-protein
#19
De Dong, Minghui Guo, Sihan Wang, Yuwei Zhu, Shuo Wang, Zhi Xiong, Jianzheng Yang, Zengliang Xu, Zhiwei Huang
CRISPR-Cas9 systems are bacterial adaptive immune systems that defend against infection by phages. Through the RNA-guided endonuclease activity of Cas9 they degrade double-stranded DNA with a protospacer adjacent motif (PAM) and sequences complementary to the guide RNA. Recently, two anti-CRISPR proteins (AcrIIA2 and AcrIIA4 from Listeria monocytogenes prophages) were identified, both of which inhibit Streptococcus pyogenes Cas9 (SpyCas9) and L. monocytogenes Cas9 activity in bacteria and human cells. However, the mechanism of AcrIIA2- or AcrIIA4-mediated Cas9 inhibition remains unknown...
June 15, 2017: Nature
https://www.readbyqxmd.com/read/28437394/selective-degradation-of-splicing-factor-caper%C3%AE-by-anticancer-sulfonamides
#20
Taisuke Uehara, Yukinori Minoshima, Koji Sagane, Naoko Hata Sugi, Kaoru Ogawa Mitsuhashi, Noboru Yamamoto, Hiroshi Kamiyama, Kentaro Takahashi, Yoshihiko Kotake, Mai Uesugi, Akira Yokoi, Atsushi Inoue, Taku Yoshida, Miyuki Mabuchi, Akito Tanaka, Takashi Owa
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4(DCAF15) mediated ubiquitination in human cancer cell lines...
June 2017: Nature Chemical Biology
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