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https://www.readbyqxmd.com/read/28720717/sting-is-an-essential-mediator-of-the-ku70-mediated-production-of-ifn-%C3%AE-1-in-response-to-exogenous-dna
#1
Hongyan Sui, Ming Zhou, Hiromi Imamichi, Xiaoli Jiao, Brad T Sherman, H Clifford Lane, Tomozumi Imamichi
We previously identified Ku70, a subunit of a DNA repair protein complex, as a cytosolic DNA sensor that induces the production of interferon-λ1 (IFN-λ1) by human primary cells and cell lines. IFN-λ1 is a type III IFN and has similar antiviral activity to that of the type I IFNs (IFN-α and IFN-β). We observed that human embryonic kidney (HEK) 293T cells, which are deficient in the innate immune adaptor protein STING (stimulator of IFN genes), did not produce IFN-λ1 in response to DNA unless they were reconstituted with STING...
July 18, 2017: Science Signaling
https://www.readbyqxmd.com/read/28717247/characterization-of-hiv-1-integrase-interaction-with-human-ku70-protein-and-initial-implications-for-drug-targeting
#2
Andrey N Anisenko, Ekaterina S Knyazhanskaya, Artur O Zalevsky, Julia Yu Agapkina, Aleksander I Sizov, Timofey S Zatsepin, Marina B Gottikh
Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with integrase from prototype foamy virus was observed. By analyzing protein subdomains we determined two binding sites in the structure of both Ku70 and integrase: the 51-160 a.a. region of integrase interacts with residues 251-438 of Ku70, whereas Ku70 N-terminal domain (1-250 a...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28712728/hexim1-and-neat1-long-non-coding-rna-form-a-multi-subunit-complex-that-regulates-dna-mediated-innate-immune-response
#3
Mehdi Morchikh, Alexandra Cribier, Raoul Raffel, Sonia Amraoui, Julien Cau, Dany Severac, Emeric Dubois, Olivier Schwartz, Yamina Bennasser, Monsef Benkirane
The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly...
July 10, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28674407/hdac6-a-novel-histone-deacetylase-implicated-in-pulmonary-arterial-hypertension
#4
Olivier Boucherat, Sophie Chabot, Roxane Paulin, Isabelle Trinh, Alice Bourgeois, François Potus, Marie-Claude Lampron, Caroline Lambert, Sandra Breuils-Bonnet, Valérie Nadeau, Renée Paradis, Elena A Goncharova, Steeve Provencher, Sébastien Bonnet
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a "cancer-like" pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH...
July 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28657072/development-of-a-crispr-cas9-system-for-efficient-genome-editing-of-candida-lusitaniae
#5
Emily L Norton, Racquel K Sherwood, Richard J Bennett
Candida lusitaniae is a member of the Candida clade that includes a diverse group of fungal species relevant to both human health and biotechnology. This species exhibits a full sexual cycle to undergo interconversion between haploid and diploid forms. C. lusitaniae is also an emerging opportunistic pathogen that can cause serious bloodstream infections in the clinic and yet has often proven to be refractory to facile genetic manipulations. In this work, we develop a clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (Cas9) system to enable genome editing of C...
May 2017: MSphere
https://www.readbyqxmd.com/read/28652322/cryo-em-structure-of-the-dna-pk-holoenzyme
#6
Humayun Sharif, Yang Li, Yuanchen Dong, Liyi Dong, Wei Li Wang, Youdong Mao, Hao Wu
DNA-dependent protein kinase (DNA-PK) is a large protein complex central to the nonhomologous end joining (NHEJ) DNA-repair pathway. It comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer of DNA-binding proteins Ku70 and Ku80. Here, we report the cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs at 4.4-Å resolution and the DNA-PK holoenzyme at 5.8-Å resolution. The DNA-PKcs structure contains three distinct segments: the N-terminal region with an arm and a bridge, the circular cradle, and the head that includes the kinase domain...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28645898/dna-pk-facilitates-piggybac-transposition-by-promoting-paired-end-complex-formation
#7
Yan Jin, Yaohui Chen, Shimin Zhao, Kun-Liang Guan, Yuan Zhuang, Wenhao Zhou, Xiaohui Wu, Tian Xu
The involvement of host factors is critical to our understanding of underlying mechanisms of transposition and the applications of transposon-based technologies. Modified piggyBac (PB) is one of the most potent transposon systems in mammals. However, varying transposition efficiencies of PB among different cell lines have restricted its application. We discovered that the DNA-PK complex facilitates PB transposition by binding to PB transposase (PBase) and promoting paired-end complex formation. Mass spectrometry analysis and coimmunoprecipitation revealed physical interaction between PBase and the DNA-PK components Ku70, Ku80, and DNA-PKcs Overexpression or knockdown of DNA-PK components enhances or suppresses PB transposition in tissue culture cells, respectively...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28641126/dna-requirements-for-interaction-of-the-c-terminal-region-of-ku80-with-the-dna-dependent-protein-kinase-catalytic-subunit-dna-pkcs
#8
Sarvan Kumar Radhakrishnan, Susan P Lees-Miller
Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks (DSBs) in human cells. Critical to NHEJ is the DNA-dependent interaction of the Ku70/80 heterodimer with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme. However, precisely how Ku recruits DNA-PKcs to DSBs ends to enhance its kinase activity has remained enigmatic, with contradictory findings reported in the literature. Here we address the role of the Ku80 C-terminal region (CTR) in the DNA-dependent interaction of Ku70/80 with DNA-PKcs using purified components and defined DNA structures...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28611389/nuclear-tradd-prevents-dna-damage-mediated-death-by-facilitating-non-homologous-end-joining-repair
#9
Gi-Bang Koo, Jae-Hoon Ji, Hyeseong Cho, Michael J Morgan, You-Sun Kim
TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, the underlying function of nuclear TRADD is poorly understood. Here we demonstrate that cytoplasmic TRADD translocates to DNA double-strand break sites (DSBs) during the DNA damage response (DDR). Deficiency of TRADD or its sequestration in cytosol leads to accumulation of γH2AX-positive foci in response to DNA damage, which is reversed by nuclear TRADD expression...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28604675/identification-of-the-elementary-structural-units-of-the-dna-damage-response
#10
Francesco Natale, Alexander Rapp, Wei Yu, Andreas Maiser, Hartmann Harz, Annina Scholl, Stephan Grulich, Tobias Anton, David Hörl, Wei Chen, Marco Durante, Gisela Taucher-Scholz, Heinrich Leonhardt, M Cristina Cardoso
Histone H2AX phosphorylation is an early signalling event triggered by DNA double-strand breaks (DSBs). To elucidate the elementary units of phospho-H2AX-labelled chromatin, we integrate super-resolution microscopy of phospho-H2AX during DNA repair in human cells with genome-wide sequencing analyses. Here we identify phospho-H2AX chromatin domains in the nanometre range with median length of ∼75 kb. Correlation analysis with over 60 genomic features shows a time-dependent euchromatin-to-heterochromatin repair trend...
June 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28578657/in-vivo-screening-reveals-interactions-between-drosophila-manf-and-genes-involved-in-the-mitochondria-and-the-ubiquinone-synthesis-pathway
#11
Riitta Lindström, Päivi Lindholm, Mari Palgi, Mart Saarma, Tapio I Heino
BACKGROUND: Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF) form an evolutionarily conserved family of neurotrophic factors. Orthologues for MANF/CDNF are the only neurotrophic factors as yet identified in invertebrates with conserved amino acid sequence. Previous studies indicate that mammalian MANF and CDNF support and protect brain dopaminergic system in non-cell-autonomous manner. However, MANF has also been shown to function intracellularly in the endoplasmic reticulum...
June 2, 2017: BMC Genetics
https://www.readbyqxmd.com/read/28567015/usp22-induces-cisplatin-resistance-in-lung-adenocarcinoma-by-regulating-%C3%AE-h2ax-mediated-dna-damage-repair-and-ku70-bax-mediated-apoptosis
#12
Aman Wang, Zhen Ning, Chang Lu, Wei Gao, Jinxiao Liang, Qiu Yan, Guang Tan, Jiwei Liu
Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22) with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28550350/recent-advances-in-the-study-of-immunodeficiency-and-dna-damage-response
#13
REVIEW
Tomohiro Morio
DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome...
May 26, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28490747/structural-basis-for-importin-%C3%AE-binding-of-the-human-immunodeficiency-virus-tat
#14
K M Smith, Z Himiari, S Tsimbalyuk, J K Forwood
HIV-1 has caused 35 million deaths globally, and approximately the same number is currently living with HIV-1. The trans-activator of transcription (Tat) protein of HIV-1 plays an important regulatory function in the virus life cycle, responsible for regulating the reverse transcription of the viral genome RNA. Tat is found in the nucleus of infected cells, but can also invade uninfected neighbouring cells. Regions within Tat responsible for these cellular localisations are overlapping and include a nuclear localisation signal (NLS) spanning (48)GRKKRR, and a cell penetrating peptide (CPP) signal spanning (48)GRKKRRQRRRAPQN...
May 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28484116/highly-efficient-gene-targeting-in-aspergillus-oryzae-industrial-strains-under-ligd-mutation-introduced-by-genome-editing-strain-specific-differences-in-the-effects-of-deleting-ecdr-the-negative-regulator-of-sclerotia-formation
#15
Hidetoshi Nakamura, Takuya Katayama, Tomoya Okabe, Kazuhiro Iwashita, Wataru Fujii, Katsuhiko Kitamoto, Jun-Ichi Maruyama
Numerous strains of Aspergillus oryzae are industrially used for Japanese traditional fermentation and for the production of enzymes and heterologous proteins. In A. oryzae, deletion of the ku70 or ligD genes involved in non-homologous end joining (NHEJ) has allowed high gene targeting efficiency. However, this strategy has been mainly applied under the genetic background of the A. oryzae wild strain RIB40, and it would be laborious to delete the NHEJ genes in many A. oryzae industrial strains, probably due to their low gene targeting efficiency...
May 2, 2017: Journal of General and Applied Microbiology
https://www.readbyqxmd.com/read/28471392/taking-a-bad-turn-compromised-dna-damage-response-in-leukemia
#16
REVIEW
Nadine Nilles, Birthe Fahrenkrog
Genomic integrity is of outmost importance for the survival at the cellular and the organismal level and key to human health. To ensure the integrity of their DNA, cells have evolved maintenance programs collectively known as the DNA damage response. Particularly challenging for genome integrity are DNA double-strand breaks (DSB) and defects in their repair are often associated with human disease, including leukemia. Defective DSB repair may not only be disease-causing, but further contribute to poor treatment outcome and poor prognosis in leukemia...
May 4, 2017: Cells
https://www.readbyqxmd.com/read/28451577/expression-levels-of-two-dna-repair-related-genes-under-8-gy-ionizing-radiation-and-100-mg-kg-melatonin-delivery-in-rat-peripheral-blood
#17
M Valizadeh, A Shirazi, P Izadi, J Tavakkoly Bazzaz, H Rezaeejam
BACKGROUND: After radiation therapy (RT), some health hazards including DNA damages may occur where melatonin can play a protective role due to free radical generation. On the other hand, serious accidental overexposures may occur during RT due to nuclear accidents which necessitate the need for study on exposure to high-dose radiations during treatments. OBJECTIVE: The aim of this study was to study the expression level of two genes in non-homologous end joining (NHEJ) pathways named Xrcc4 and Xrcc6 (Ku70) in order to examine the effect of melatonin on repair of DNA double-strand breaks (BSBs) caused by 8Gy ionizing radiation...
March 2017: Journal of Biomedical Physics & Engineering
https://www.readbyqxmd.com/read/28415827/camptothecin-resistance-is-determined-by-the-regulation-of-topoisomerase-i-degradation-mediated-by-ubiquitin-proteasome-pathway
#18
Koji Ando, Ankur K Shah, Vibhu Sachdev, Benjamin P Kleinstiver, Julian Taylor-Parker, Moira M Welch, Yiheng Hu, Ravi Salgia, Forest M White, Jeffrey D Parvin, Al Ozonoff, Lucia E Rameh, J Keith Joung, Ajit K Bharti
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28289912/production-of-%C3%AE-carotene-by-expressing-a-heterologous-multifunctional-carotene-synthase-in-yarrowia-lipolytica
#19
Shuliang Gao, Yangyang Tong, Li Zhu, Mei Ge, Yu Jiang, Daijie Chen, Sheng Yang
OBJECTIVES: To obtain functional expression of a heterologous multifunctional carotene synthase containing phytoene synthase, phytoene dehydrogenase, and lycopene β-cyclase activities encoded by carS from Schizochytrium sp. in order to allow Yarrowia lipolytica to produce β-carotene. RESULTS: To increase the integration efficiency of a 3.8 kb carS under the control of P GPD promoter with a 2 kb selection marker, ura3, along with a geranylgeranyl diphosphate synthase (GGS1) expression cassette (~10 kb in total), was inserted into the Y...
March 13, 2017: Biotechnology Letters
https://www.readbyqxmd.com/read/28267674/the-effects-of-saha-on-radiosensitivity-in-pancreatic-cancer-cells-by-inducing-apoptosis-and-targeting-rad51
#20
Zhibing Wu, Saisai Jing, Yanhong Li, Yabo Gao, Shuhuan Yu, Zhitian Li, Yanyan Zhao, Jigang Piao, Shenglin Ma, Xufeng Chen
Suberoyl anilide hydroxamic acid (SAHA) is one of the most promising Histone deacetylases(HDAC) inhibitors which has shown significant anti-tumor activity for many malignancies. We explored the potential mechanism of the radiosensitivity effect of SAHA in Panc-1 cells and attempted to develop SAHA as a systemic treatment strategy for pancreatic cancer. Growth inhibition was detected by CCK-8 assay. Radiosensitizing enhancement ratio was determined by clonogenic assay. The cell cycle and apoptosis assay was detected using flow cytometry and annexin-V/PI...
May 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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