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non-homologous end joining

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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
#1
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/28634159/a-role-for-the-nonsense-mediated-mrna-decay-pathway-in-maintaining-genome-stability-in-caenorhabditis-elegans
#2
Víctor González-Huici, Bin Wang, Anton Gartner
Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand-breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hypersensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) kinase involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signalling pathways...
June 20, 2017: Genetics
https://www.readbyqxmd.com/read/28631016/new-insights-into-cohesin-loading
#3
REVIEW
Ireneusz Litwin, Robert Wysocki
Cohesin is a conserved, ring-shaped protein complex that encircles sister chromatids and ensures correct chromosome segregation during mitosis and meiosis. It also plays a crucial role in the regulation of gene expression, DNA condensation, and DNA repair through both non-homologous end joining and homologous recombination. Cohesins are spatiotemporally regulated by the Scc2-Scc4 complex which facilitates cohesin loading onto chromatin at specific chromosomal sites. Over the last few years, much attention has been paid to cohesin and cohesin loader as it became clear that even minor disruptions of these complexes may lead to developmental disorders and cancers...
June 19, 2017: Current Genetics
https://www.readbyqxmd.com/read/28625156/heteroduplex-cleavage-assay-for-screening-of-probable-zygosities-resulting-from-crispr-mutations-in-diploid-single-cell-lines
#4
Kyle D Luttgeharm, Kit-Sum Wong, Steve Siembieda
The most common gene editing methods, such as CRISPR, involve random repair of an induced double-stranded DNA break through the non-homologous end joining (NHEJ) repair pathway, resulting in small insertions/deletions. In diploid cells, these mutations can take on one of three zygosities: monoallelic, diallelic heterozygous, or diallelic homozygous. While many advances have been made in CRISPR delivery systems and gene editing efficiency, little work has been done to streamline detection of gene editing events...
June 1, 2017: BioTechniques
https://www.readbyqxmd.com/read/28624371/histone-ubiquitination-in-the-dna-damage-response
#5
REVIEW
Michael Uckelmann, Titia K Sixma
DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28624224/optimizing-the-dna-donor-template-for-homology-directed-repair-of-double-strand-breaks
#6
Fei Song, Knut Stieger
The CRISPR-Cas (clustered regularly interspaced short palindromic repeats-associated proteins) technology enables rapid and precise genome editing at any desired genomic position in almost all cells and organisms. In this study, we analyzed the impact of different repair templates on the frequency of homology-directed repair (HDR) and non-homologous end joining (NHEJ). We used a stable HEK293 cell line expressing the traffic light reporter (TLR-3) system to quantify HDR and NHEJ events following transfection with Cas9, eight different guide RNAs, and a 1,000 bp donor template generated either as circular plasmid, as linearized plasmid with long 3' or 5' backbone overhang, or as PCR product...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624213/crispr-cas9-loxp-mediated-gene-editing-as-a-novel-site-specific-genetic-manipulation-tool
#7
Fayu Yang, Changbao Liu, Ding Chen, Mengjun Tu, Haihua Xie, Huihui Sun, Xianglian Ge, Lianchao Tang, Jin Li, Jiayong Zheng, Zongming Song, Jia Qu, Feng Gu
Cre-loxP, as one of the site-specific genetic manipulation tools, offers a method to study the spatial and temporal regulation of gene expression/inactivation in order to decipher gene function. CRISPR/Cas9-mediated targeted genome engineering technologies are sparking a new revolution in biological research. Whether the traditional site-specific genetic manipulation tool and CRISPR/Cas9 could be combined to create a novel genetic tool for highly specific gene editing is not clear. Here, we successfully generated a CRISPR/Cas9-loxP system to perform gene editing in human cells, providing the proof of principle that these two technologies can be used together for the first time...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624204/crispr-cas9-directed-reassignment-of-the-gata1-initiation-codon-in-k562-cells-to-recapitulate-aml-in-down-syndrome
#8
Kevin M Bloh, Pawel A Bialk, Anilkumar Gopalakrishnapillai, E Anders Kolb, Eric B Kmiec
Using a CRISPR/Cas9 system, we have reengineered a translational start site in the GATA1 gene in K562 cells. This mutation accounts largely for the onset of myeloid leukemia in Down syndrome (ML-DS). For this reengineering, we utilized CRISPR/Cas9 to generate mammalian cell lines that express truncated versions of the Gata1s protein similar to that seen in ML-DS, as determined by analyzing specific genetic alterations resulting from CRISPR/Cas9 cleavage. During this work, 73 cell lines were clonally expanded, with allelic variance analyzed...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28623876/developmental-history-and-application-of-crispr-in-human-disease
#9
REVIEW
Puping Liang, Xiya Zhang, Yuxi Chen, Junjiu Huang
Genome editing tools are programmable artificial nucleases, mainly including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR). By recognizing and cleaving specific DNA sequences, genome editing tools make it possible to generate site-specific DNA double-strand breaks (DSBs) in the genome. DSBs will then be repaired by either error-prone non-homologous end joining (NHEJ) or high-fidelity homologous recombination (HR) mechanisms...
June 17, 2017: Journal of Gene Medicine
https://www.readbyqxmd.com/read/28619647/using-crispr-cas9-to-generate-gene-corrected-autologous-ipscs-for-the-treatment-of-inherited-retinal-degeneration
#10
Erin R Burnight, Manav Gupta, Luke A Wiley, Kristin R Anfinson, Audrey Tran, Robinson Triboulet, Jeremy M Hoffmann, Darcey L Klaahsen, Jeaneen L Andorf, Chunhua Jiao, Elliott H Sohn, Malavika K Adur, Jason W Ross, Robert F Mullins, George Q Daley, Thorsten M Schlaeger, Edwin M Stone, Budd A Tucker
Patient-derived induced pluripotent stem cells (iPSCs) hold great promise for autologous cell replacement. However, for many inherited diseases, treatment will likely require genetic repair pre-transplantation. Genome editing technologies are useful for this application. The purpose of this study was to develop CRISPR-Cas9-mediated genome editing strategies to target and correct the three most common types of disease-causing variants in patient-derived iPSCs: (1) exonic, (2) deep intronic, and (3) dominant gain of function...
June 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28612261/low-concentrations-of-antimony-impair-dna-damage-signaling-and-the-repair-of-radiation-induced-dsb-in-hela-s3-cells
#11
Barbara Koch, Elena Maser, Andrea Hartwig
Antimony is utilized in a large variety of industrial applications, leading to significant environmental and occupational exposure. Mainly based on animal experiments, the IARC and MAK Commission have classified antimony and its inorganic compounds as Group 2B or 2 carcinogens, respectively. However, the underlying mode(s) of action are still largely unknown. In the present study, we investigated the impact of non-cytotoxic up to cytotoxic concentrations of SbCl3 on DNA DSB repair and cell cycle control in HeLa S3 cells...
June 13, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28611389/nuclear-tradd-prevents-dna-damage-mediated-death-by-facilitating-non-homologous-end-joining-repair
#12
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/28606356/deletion-of-ligd-significantly-improves-gene-targeting-frequency-in-the-lignocellulolytic-filamentous-fungus-penicillium-oxalicum
#13
Xiulin Qin, Ruijie Li, Xiang Luo, Yanmei Lin, Jia-Xun Feng
To improve the gene targeting frequency (GTF) in the lignocellulolytic filamentous fungus Penicillium oxalicum HP7-1, the non-homologous end-joining (NHEJ) gene ligD was deleted. The obtained PoligD deletion mutant ΔPoligD showed no apparent defect in cellulase production, growth rate, and sensitivity towards osmotic stress and mutagen ethyl methanesulphonate (EMS), while increased sensitivity to high concentrations of methyl methanesulfonate (MMS). Deletion of PoligD gene resulted in significantly increased GTFs at three different loci in P...
June 2017: Fungal Biology
https://www.readbyqxmd.com/read/28604711/the-anaphase-promoting-complex-impacts-repair-choice-by-protecting-ubiquitin-signalling-at-dna-damage-sites
#14
Kyungsoo Ha, Chengxian Ma, Han Lin, Lichun Tang, Zhusheng Lian, Fang Zhao, Ju-Mei Li, Bei Zhen, Huadong Pei, Suxia Han, Marcos Malumbres, Jianping Jin, Huan Chen, Yongxiang Zhao, Qing Zhu, Pumin Zhang
Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). While HDR can only occur in S/G2, NHEJ can happen in all cell cycle phases (except mitosis). How then is the repair choice made in S/G2 cells? Here we provide evidence demonstrating that APC(Cdh1) plays a critical role in choosing the repair pathways in S/G2 cells. Our results suggest that the default for all DSBs is to recruit 53BP1 and RIF1. BRCA1 is blocked from being recruited to broken ends because its recruitment signal, K63-linked poly-ubiquitin chains on histones, is actively destroyed by the deubiquitinating enzyme USP1...
June 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28599495/investigation-of-the-relative-biological-effectiveness-and-uniform-isobiological-killing-effects-of-irradiation-with-a-clinical-carbon-sobp-beam-on-dna-repair-deficient-cho-cells
#15
Shigeaki Sunada, Ian M Cartwright, Hirokazu Hirakawa, Akira Fujimori, Mitsuru Uesaka, Takamitsu A Kato
Spread-out Bragg peak (SOBP) C ions have been used clinically in charged particle radiation therapy for years. An SOBP beam consists of various monoenergetic Bragg peaks; however, the biological effect of irradiation with an SOBP beam track has not been well-studied. In order to determine the clinically prospective molecular targets, radiosensitivity to the beam track in DNA repair deficient cell lines was investigated. A total of four distinct Chinese hamster ovary (CHO) cell lines, including CHO10B2 (wild-type), V3 (protein kinase DNA-activated catalytic polypeptide deficient), 51D1 (RAD51 paralog D deficient) and PADR9 [poly(ADP-ribose) polymerase (PARP) deficient], were irradiated with gamma-rays, C ions (290 MeV/n) and Fe ions (500 MeV/n), in order to compare cellular lethality...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28594094/the-application-of-crispr-cas-technology-to-efficiently-model-complex-cancer-genomes-in-stem-cells
#16
Adam Albitar, Bahar Rohani, Brett Will, Annie Yan, G Ian Gallicano
CRISPR/Cas gene editing technologies have emerged as powerful tools in the study of oncogenic transformation. The system's specificity, versatility, and ease of implementation allow researchers to identify important molecular markers and pathways which grant cancers stem cell like properties. This technology has already been applied to researching specific cancers, but has seen restricted therapeutic applications due to inherent ethical and technical limitations. Active development and adaptation of the CRISPR/Cas system has produced new methods to take advantage of both non-homologous end joining and homologous recombination repair mechanisms in attempts to remedy these limitations and improve the versatility of gene edits that can be created...
June 8, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28589393/a-history-of-genome-editing-in-mammals
#17
Almudena Fernández, Santiago Josa, Lluis Montoliu
Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly short but intense history of genome-editing approaches illustrates how a disruptive technology can universally colonize a field when this new methodology, conceived to alter mammalian genomes at specific locations, is found to efficiently and robustly deliver results. This review summarizes the early development of genome editing using nucleases, from the pioneering experiments using yeast meganucleases, to the latest prokaryotic nucleases used for precise genome manipulation...
June 6, 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/28589392/naming-crispr-alleles-endonuclease-mediated-mutation-nomenclature-across-species
#18
Michelle N Knowlton, Cynthia L Smith
The widespread use of CRISPR/Cas and other targeted endonuclease technologies in many species has led to an explosion in the generation of new mutations and alleles. The ability to generate many different mutations from the same target sequence either by homology-directed repair with a donor sequence or non-homologous end joining-induced insertions and deletions necessitates a means for representing these mutations in literature and databases. Standardized nomenclature can be used to generate unambiguous, concise, and specific symbols to represent mutations and alleles...
June 6, 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/28587922/molecular-basis-for-k63-linked-ubiquitination-processes-in-double-strand-dna-break-repair-a-focus-on-kinetics-and-dynamics
#19
REVIEW
Brian L Lee, Anamika, J N Mark Glover, Michael J Hendzel, Leo Spyracopoulos
Cells are exposed to thousands of DNA damage events on a daily basis. This damage must be repaired to preserve genetic information, and prevent development of disease. The most deleterious damage is a double strand break (DSB), which is detected and repaired by mechanisms known as non-homologous end joining (NHEJ), and homologous recombination (HR), components of the DNA damage response system. NHEJ is an error prone first line of defense, whereas HR invokes error free repair, and is the focus of this review...
June 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28584163/protection-of-arabidopsis-blunt-ended-telomeres-is-mediated-by-a-physical-association-with-the-ku-heterodimer
#20
Sona Valuchova, Jaroslav Fulnecek, Zbynek Prokop, Paggy Stolt-Bergner, Eliska Janouskova, Ctirad Hofr, Karel Riha
Telomeres form specialized chromatin that protects natural chromosome termini from being recognized as DNA double-strand breaks. Plants possess unusual blunt-ended telomeres that are unable to form t-loops or complex with single-strand DNA binding proteins, raising the question of the mechanism behind their protection. We have previously suggested that blunt-ended telomeres in Arabidopsis thaliana are protected by Ku, a DNA repair factor with a high affinity for DNA ends. In non-homologous end joining (NHEJ), Ku loads onto broken DNA via a channel consisting of positively charged amino acids...
June 5, 2017: Plant Cell
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