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non-homologous end-joining

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https://www.readbyqxmd.com/read/29438517/genome-editing-in-kluyveromyces-and-ogataea-yeasts-using-a-broad-host-range-cas9-grna-co-expression-plasmid
#1
Hannes Juergens, Javier A Varela, Arthur R Gorter de Vries, Thomas Perli, Veronica J M Gast, Nikola Y Gyurchev, Arun S Rajkumar, Robert Mans, Jack T Pronk, John P Morrissey, Jean-Marc G Daran
While CRISPR-Cas9-mediated genome editing has transformed yeast research, current plasmids and cassettes for Cas9 and guide-RNA expression are species specific. CRISPR tools that function in multiple yeast species could contribute to the intensifying research on non-conventional yeasts. A plasmid carrying a pangenomic origin of replication and two constitutive expression cassettes, for Cas9 and a ribozyme-flanked gRNAs was constructed. Its functionality was tested by analyzing inactivation of the ADE2 gene in four yeast species...
February 9, 2018: FEMS Yeast Research
https://www.readbyqxmd.com/read/29430654/enhanced-efficacy-of-azd3759-and-radiation-on-brain-metastasis-from-egfr-mutant-non-small-cell-lung-cancer
#2
Xue Li, Yingchun Wang, Jia Wang, Tianwei Zhang, Li Zheng, Zhenfan Yang, Ligang Xing, Jinming Yu
The prognosis of patients with brain metastasis (BM) is poor. In this study, we demonstrated that AZD3759, an EGFR tyrosine kinase inhibitors (TKIs) with excellent blood-brain barrier (BBB) penetration, combined with radiation enhanced the antitumor efficacy in BM model from EGFR mutant (EGFRm) NSCLC. Besides, the antitumor activity displayed no difference between radiation concurrently with AZD3759 and radiation sequentially with AZD3759. Mechanistically, we found that two factors determined the enhanced efficacy: cells with EGFRm which were sensitive to AZD3759, and a relative high concentration of AZD3759...
February 12, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29428683/dna-repair-mechanisms-in-response-to-genotoxicity-of-warfare-agent-sulfur-mustard
#3
REVIEW
Yunes Panahi, Amir Fattahi, Hamid Reza Nejabati, Sina Abroon, Zeinab Latifi, Abolfazl Akbarzadeh, Tohid Ghasemnejad
Sulfur mustard (SM) is an alkylating agent that causes severe damages to the skin, eyes, and the respiratory system. DNA alkylation is one of the most critical lesions that could lead to monoadducts and cross-links, as well as DNA strand breaks. In response to these adducts, cells initiate a series of reactions to recruit specific DNA repair pathways. The main DNA repair pathways in human cells, which could be involved in the DNA SM-induced DNA damages, are base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ)...
February 2, 2018: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/29426373/silencing-artemis-enhances-colorectal-cancer-cell-sensitivity-to-dna-damaging-agents
#4
Hai Liu, Xuanxuan Wang, Aihua Huang, Huaping Gao, Yikan Sun, Tingting Jiang, Liming Shi, Xianjie Wu, Qinghua Dong, Xiaonan Sun
Artemis is a key protein of NHEJ (non-homologous end-joining), which is the major pathway for the repair of IR-inducedDSBs in mammalian cells. However, it has not been largely investigated about the expression of Artemis in tumor and the influence of silencing Artemis on the tumor's sensitivity to radiation. In this study, we investigated how expression levels of Artemis may affect treatment outcome of radiotherapy and chemotherapy in colorectal cancer cells. Firstly, we found that the expression of Artemis is strong in some human rectal cancer samples, even can be higher than adjacent normal tissues using immunohistochemical staining...
February 9, 2018: Oncology Research
https://www.readbyqxmd.com/read/29423214/use-of-gene-editing-technology-to-introduce-targeted-modifications-in-pigs
#5
REVIEW
Junghyun Ryu, Randall S Prather, Kiho Lee
Pigs are an important resource in agriculture and serve as a model for human diseases. Due to their physiological and anatomical similarities with humans, pigs can recapitulate symptoms of human diseases, making them a useful model in biomedicine. However, in the past pig models have not been widely used partially because of the difficulty in genetic modification. The lack of true embryonic stem cells in pigs forced researchers to utilize genetic modification in somatic cells and somatic cell nuclear transfer (SCNT) to generate genetically engineered (GE) pigs carrying site-specific modifications...
2018: Journal of Animal Science and Biotechnology
https://www.readbyqxmd.com/read/29423082/reduced-recruitment-of-53bp1-during-interstrand-crosslink-repair-is-associated-with-genetically-inherited-attenuation-of-mitomycin-c-sensitivity-in-a-family-with-fanconi-anemia
#6
Emilie Lesport, Alina Ferster, Armand Biver, Benoit Roch, Nadia Vasquez, Nada Jabado, Francina Langa Vives, Patrick Revy, Jean Soulier, Jean-Pierre de Villartay
The Fanconi anemia (FA) pathway is implicated in the repair of DNA interstrand crosslinks (ICL). In this process, it has been shown that FA factors regulate the choice for DNA double strand break repair towards homologous recombination (HR). As this mechanism is impaired in FA deficient cells exposed to crosslinking agents, an inappropriate usage of non-homologous end joining (NHEJ) leads to the accumulation of toxic chromosomal abnormalities. We studied a family with two FANCG patients and found a genetically inherited attenuation of mitomycin C sensitivity resulting in-vitro in an attenuated phenotype for one patient or in increased resistance for two healthy relatives...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29422642/in-silico-non-homologous-end-joining-following-ion-induced-dna-double-strand-breaks-predicts-that-repair-fidelity-depends-on-break-density
#7
N T Henthorn, J W Warmenhoven, M Sotiropoulos, R I Mackay, N F Kirkby, K J Kirkby, M J Merchant
This work uses Monte Carlo simulations to investigate the dependence of residual and misrepaired double strand breaks (DSBs) at 24 hours on the initial damage pattern created during ion therapy. We present results from a nanometric DNA damage simulation coupled to a mechanistic model of Non-Homologous End Joining, capable of predicting the position, complexity, and repair of DSBs. The initial damage pattern is scored by calculating the average number of DSBs within 70 nm from every DSB. We show that this local DSB density, referred to as the cluster density, can linearly predict misrepair regardless of ion species...
February 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29416038/drosha-drives-the-formation-of-dna-rna-hybrids-around-dna-break-sites-to-facilitate-dna-repair
#8
Wei-Ting Lu, Ben R Hawley, George L Skalka, Robert A Baldock, Ewan M Smith, Aldo S Bader, Michal Malewicz, Felicity Z Watts, Ania Wilczynska, Martin Bushell
The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair...
February 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29402884/target-identification-of-small-molecules-using-large-scale-crispr-cas-mutagenesis-scanning-of-essential-genes
#9
Jasper Edgar Neggers, Bert Kwanten, Tim Dierckx, Hiroki Noguchi, Arnout Voet, Lotte Bral, Kristien Minner, Bob Massant, Nicolas Kint, Michel Delforge, Thomas Vercruysse, Erkan Baloglu, William Senapedis, Maarten Jacquemyn, Dirk Daelemans
Unraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations...
February 5, 2018: Nature Communications
https://www.readbyqxmd.com/read/29393557/talen-mediated-gene-targeting-in-porcine-spermatogonia
#10
Lin Tang, Alla Bondareva, Raquel González, Jose Rafael Rodriguez-Sosa, Daniel F Carlson, Dennis Webster, Scott Fahrenkrug, Ina Dobrinski
Spermatogonia represent a diploid germ cell population that includes spermatogonial stem cells. In this report, we describe new methods for isolation of highly enriched porcine spermatogonia based on light scatter properties, and for targeted mutagenesis in porcine spermatogonia using nucleofection and TALENs. We optimized a nucleofection protocol to deliver TALENs specifically targeting the DMD locus in porcine spermatogonia. We also validated specific sorting of porcine spermatogonia based on light scatter properties...
February 2, 2018: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/29379011/streamlined-ex-vivo-and-in-vivo-genome-editing-in-mouse-embryos-using-recombinant-adeno-associated-viruses
#11
Yeonsoo Yoon, Dan Wang, Phillip W L Tai, Joy Riley, Guangping Gao, Jaime A Rivera-Pérez
Recent advances using CRISPR-Cas9 approaches have dramatically enhanced the ease for genetic manipulation in rodents. Notwithstanding, the methods to deliver nucleic acids into pre-implantation embryos have hardly changed since the original description of mouse transgenesis more than 30 years ago. Here we report a novel strategy to generate genetically modified mice by transduction of CRISPR-Cas9 components into pre-implantation mouse embryos via recombinant adeno-associated viruses (rAAVs). Using this approach, we efficiently generated a variety of targeted mutations in explanted embryos, including indel events produced by non-homologous end joining and tailored mutations using homology-directed repair...
January 29, 2018: Nature Communications
https://www.readbyqxmd.com/read/29367880/cytogenomic-identification-and-long-read-single-molecule-real-time-smrt-sequencing-of-a-bardet-biedl-syndrome-9-bbs9-deletion
#12
Jennifer Reiner, Laura Pisani, Wanqiong Qiao, Ram Singh, Yao Yang, Lisong Shi, Wahab A Khan, Robert Sebra, Ninette Cohen, Arvind Babu, Lisa Edelmann, Ethylin Wang Jabs, Stuart A Scott
Bardet-Biedl syndrome (BBS) is a recessive disorder characterized by heterogeneous clinical manifestations, including truncal obesity, rod-cone dystrophy, renal anomalies, postaxial polydactyly, and variable developmental delays. At least 20 genes have been implicated in BBS, and all are involved in primary cilia function. We report a 1-year-old male child from Guyana with obesity, postaxial polydactyly on his right foot, hypotonia, ophthalmologic abnormalities, and developmental delay, which together indicated a clinical diagnosis of BBS...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29364275/using-crispr-cas9-gene-editing-to-investigate-the-oncogenic-activity-of-mutant-calreticulin-in-cytokine-dependent-hematopoietic-cells
#13
Nouran S Abdelfattah, Ann Mullally
Clustered regularly interspaced short palindromic repeats (CRISPR) is an adaptive immunity system in prokaryotes that has been repurposed by scientists to generate RNA-guided nucleases, such as CRISPR-associated (Cas) 9 for site-specific eukaryotic genome editing. Genome engineering by Cas9 is used to efficiently, easily and robustly modify endogenous genes in many biomedically-relevant mammalian cell lines and organisms. Here we show an example of how to utilize the CRISPR/Cas9 methodology to understand the biological function of specific genetic mutations...
January 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29361783/localization-microscopy-analyses-of-mre11-clusters-in-3d-conserved-cell-nuclei-of-different-cell-lines
#14
Marion Eryilmaz, Eberhard Schmitt, Matthias Krufczik, Franziska Theda, Jin-Ho Lee, Christoph Cremer, Felix Bestvater, Wladimir Schaufler, Michael Hausmann, Georg Hildenbrand
In radiation biophysics, it is a subject of nowadays research to investigate DNA strand break repair in detail after damage induction by ionizing radiation. It is a subject of debate as to what makes up the cell's decision to use a certain repair pathway and how the repair machinery recruited in repair foci is spatially and temporarily organized. Single-molecule localization microscopy (SMLM) allows super-resolution analysis by precise localization of single fluorescent molecule tags, resulting in nuclear structure analysis with a spatial resolution in the 10 nm regime...
January 22, 2018: Cancers
https://www.readbyqxmd.com/read/29351627/repair-kinetics-of-dna-double-strand-breaks-and-incidence-of-apoptosis-in-mouse-neural-stem-progenitor-cells-and-their-differentiated-neurons-exposed-to-ionizing-radiation
#15
Hiroki Kashiwagi, Kazunori Shiraishi, Kenta Sakaguchi, Tomoya Nakahama, Seiji Kodama
Neuronal loss leads to neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Huntington's disease. Because of their long lifespans, neurons are assumed to possess highly efficient DNA repair ability and to be able to protect themselves from deleterious DNA damage such as DNA double-strand breaks (DSBs) produced by intrinsic and extrinsic sources. However, it remains largely unknown whether the DSB repair ability of neurons is more efficient compared with that of other cells. Here, we investigated the repair kinetics of X-ray-induced DSBs in mouse neural cells by scoring the number of phosphorylated 53BP1 foci post irradiation...
January 17, 2018: Journal of Radiation Research
https://www.readbyqxmd.com/read/29348585/a-surrogate-reporter-system-for-multiplexable-evaluation-of-crispr-cas9-in-targeted-mutagenesis
#16
Hongmin Zhang, Yuexin Zhou, Yinan Wang, Yige Zhao, Yeting Qiu, Xinyi Zhang, Di Yue, Zhuo Zhou, Wensheng Wei
Engineered nucleases in genome editing manifest diverse efficiencies at different targeted loci. There is therefore a constant need to evaluate the mutation rates at given loci. T7 endonuclease 1 (T7E1) and Surveyor mismatch cleavage assays are the most widely used methods, but they are labour and time consuming, especially when one must address multiple samples in parallel. Here, we report a surrogate system, called UDAR (Universal Donor As Reporter), to evaluate the efficiency of CRISPR/Cas9 in targeted mutagenesis...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29346775/brd4-promotes-dna-repair-and-mediates-the-formation-of-tmprss2-erg-gene-rearrangements-in-prostate-cancer
#17
Xiangyi Li, GuemHee Baek, Susmita G Ramanand, Adam Sharp, Yunpeng Gao, Wei Yuan, Jon Welti, Daniel N Rodrigues, David Dolling, Ines Figueiredo, Semini Sumanasuriya, Mateus Crespo, Adam Aslam, Rui Li, Yi Yin, Bipasha Mukherjee, Mohammed Kanchwala, Ashley M Hughes, Wendy S Halsey, Cheng-Ming Chiang, Chao Xing, Ganesh V Raj, Sandeep Burma, Johann de Bono, Ram S Mani
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29344644/inactivation-of-dna-pk-by-knockdown-dna-pkcs-or-nu7441-impairs-non-homologous-end-joining-of-radiation-induced-double-strand-break-repair
#18
Jun Dong, Yufeng Ren, Tian Zhang, Zhenyu Wang, Clifton C Ling, Gloria C Li, Fuqiu He, Chengtao Wang, Bixiu Wen
The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair...
January 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29339410/maintenance-of-genome-integrity%C3%A2-by-mi2-homologs-chd-3-and-let-418-in%C3%A2-caenorhabditis-elegans
#19
Carolyn A Turcotte, Solomon A Sloat, Julia A Rigothi, Erika Rosenkranse, Alexandra L Northrup, Nicolas P Andrews, Paula M Checchi
Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination...
January 16, 2018: Genetics
https://www.readbyqxmd.com/read/29333119/phytotherapeutics-oridonin-and-ponicidin-show-additive-effects-combined-with-irradiation-in-pancreatic-cancer-in-vitro
#20
Jakob Liermann, Patrick Naumann, Franco Fortunato, Thomas E Schmid, Klaus-Josef Weber, Jürgen Debus, Stephanie E Combs
Background: Chemoradiation of locally advanced non-metastatic pancreatic cancer can lead to secondary operability by tumor mass reduction. Here, we analyzed radiomodulating effects of oridonin and ponicidin in pancreatic cancer in vitro. Both agents are ent-kaurane diterpenoids, extracted from Isodon rubescens, a plant that is well known in Traditional Chinese Medicine. Cytotoxic effects have recently been shown in different tumor entities for both agents. Materials and methods: Pancreatic cancer cell lines AsPC-1, BxPC-3, Panc-1 and MIA PaCa-2 were pretreated with oridonin or ponicidin and irradiated with 2 Gy to 6 Gy...
December 2017: Radiology and Oncology
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