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non-homologous end-joining

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https://www.readbyqxmd.com/read/28526069/xlf-mediated-nhej-activity-in-hepatocellular-carcinoma-therapy-resistance
#1
Sitian Yang, Xiao Qi Wang
BACKGROUND: DNA repair pathways are used by cancer cells to overcome many standard anticancer treatments, causing therapy resistance. Here, we investigated the role of XRCC4-like factor (XLF), a core member of the non-homologous end joining (NHEJ) repair pathway, in chemoresistance in hepatocellular carcinoma (HCC). METHODS: qRT-PCR analysis and western blotting were performed to detect expression levels of genes and proteins related to NHEJ. NHEJ repair capacity was assessed in vitro (cell-free) and in vivo by monitoring the activity of the NHEJ pathway...
May 19, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28524166/homology-mediated-end-joining-based-targeted-integration-using-crispr-cas9
#2
Xuan Yao, Xing Wang, Xinde Hu, Zhen Liu, Junlai Liu, Haibo Zhou, Xiaowen Shen, Yu Wei, Zijian Huang, Wenqin Ying, Yan Wang, Yan-Hong Nie, Chen-Chen Zhang, Sanlan Li, Leping Cheng, Qifang Wang, Yan Wu, Pengyu Huang, Qiang Sun, Linyu Shi, Hui Yang
Targeted integration of transgenes can be achieved by strategies based on homologous recombination (HR), microhomology-mediated end joining (MMEJ) or non-homologous end joining (NHEJ). The more generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining (HMEJ)-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and ∼800 bp of homology arms, and the targeted genome...
May 19, 2017: Cell Research
https://www.readbyqxmd.com/read/28522325/generation-of-chromosomal-translocations-that-lead-to-conditional-fusion-protein-expression-using-crispr-cas9-and-homology-directed-repair
#3
Fabio Vanoli, Maria Jasin
Recurrent chromosomal translocations often lead to expression of fusion proteins associated with oncogenic transformation. To study translocations and downstream events, genome editing techniques have been developed to generate chromosomal translocations through non-homologous end joining of DNA double-strand breaks introduced at the two participating endogenous loci. However, the frequencies at which these events occur is usually too low to efficiently clone cells carrying the translocation. This article provides a detailed method using CRISPR-Cas9 technology and homology-directed repair to efficiently isolate cells harboring a chromosomal translocation...
May 15, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28515316/dna-damage-induced-degradation-of-exo1-limits-dna-end-resection-to-ensure-accurate-dna-repair
#4
Nozomi Tomimatsu, Bipasha Mukherjee, Janelle Louise Harris, Francesca Ludovica Boffo, Molly Hardebeck, Patrick Ryan Potts, Kum Kum Khanna, Sandeep Burma
End resection of DNA double-strand breaks (DSBs) to generate 3'-single-stranded DNA facilitates DSB repair via error-free homologous recombination (HR) while stymieing repair by the error-prone non-homologous end joining (NHEJ) pathway. Activation of DNA end resection involves phosphorylation of the 5' to 3' exonuclease EXO1 by the phosphoinositide 3-kinase-like kinases ATM and ATR, and by the cyclin-dependent kinases 1 and 2. After activation, EXO1 must also be restrained in order to prevent over-resection which is known to hamper optimal HR and trigger global genomic instability...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28512351/non-homologous-dna-end-joining-and-alternative-pathways-to-double-strand-break-repair
#5
REVIEW
Howard H Y Chang, Nicholas R Pannunzio, Noritaka Adachi, Michael R Lieber
DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions. In all mammalian cells, DSBs that occur throughout the cell cycle are repaired predominantly by the non-homologous DNA end joining (NHEJ) pathway. Defects in NHEJ result in sensitivity to ionizing radiation and the ablation of lymphocytes. The NHEJ pathway utilizes proteins that recognize, resect, polymerize and ligate the DNA ends in a flexible manner. This flexibility permits NHEJ to function on a wide range of DNA-end configurations, with the resulting repaired DNA junctions often containing mutations...
May 17, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28507545/clinical-and-molecular-heterogeneity-of-rtel1-deficiency
#6
Carsten Speckmann, Sushree Sangita Sahoo, Marta Rizzi, Shinsuke Hirabayashi, Axel Karow, Nina Kathrin Serwas, Marc Hoemberg, Natalja Damatova, Detlev Schindler, Jean-Baptiste Vannier, Simon J Boulton, Ulrich Pannicke, Gudrun Göhring, Kathrin Thomay, J J Verdu-Amoros, Holger Hauch, Wilhelm Woessmann, Gabriele Escherich, Eckart Laack, Liliana Rindle, Maximilian Seidl, Anne Rensing-Ehl, Ekkehart Lausch, Christine Jandrasits, Brigitte Strahm, Klaus Schwarz, Stephan R Ehl, Charlotte Niemeyer, Kaan Boztug, Marcin W Wlodarski
Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28500754/mutational-phospho-mimicry-reveals-a-regulatory-role-for-the-xrcc4-and-xlf-c-terminal-tails-in-modulating-dna-bridging-during-classical-non-homologous-end-joining
#7
Davide Normanno, Aurélie Négrel, Abinadabe J de Melo, Stéphane Betzi, Katheryn Meek, Mauro Modesti
XRCC4 and DNA Ligase 4 (LIG4) form a tight complex that provides DNA ligase activity for classical non-homologous end joining (the predominant DNA double-strand break repair pathway in higher eukaryotes) and is stimulated by XLF. Independently of LIG4, XLF also associates with XRCC4 to form filaments that bridge DNA. These XRCC4/XLF complexes rapidly load and connect broken DNA, thereby stimulating intermolecular ligation. XRCC4 and XLF both include disordered C-terminal tails that are functionally dispensable in isolation but are phosphorylated in response to DNA damage by DNA-PK and/or ATM...
May 13, 2017: ELife
https://www.readbyqxmd.com/read/28499832/versatile-and-precise-gene-targeting-strategies-for-functional-studies-in-mammalian-cell-lines
#8
REVIEW
M Wassef, A Luscan, A Battistella, S Le Corre, H Li, M R Wallace, M Vidaud, R Margueron
The advent of programmable nucleases such as ZFNs, TALENs and CRISPR/Cas9 has brought the power of genetic manipulation to widely used model systems. In mammalian cells, nuclease-mediated DNA double strand break is mainly repaired through the error-prone non-homologous end-joining (NHEJ) repair pathway, eventually leading to accumulation of small deletions or insertions (indels) that can inactivate gene function. However, due to the variable size of the indels and the polyploid status of many cell lines (e...
May 10, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28498430/uva-induced-upregulation-of-progerin-suppresses-53bp1%C3%A2-mediated-nhej-dsb-repair-in-human-keratinocytes-via-progerin-lamin%C3%A2-a-complex-formation
#9
Xin Huang, Yun Pan, Di Cao, Sheng Fang, Kun Huang, Jin Chen, Aijun Chen
Ultraviolet (UV) radiation is the primary risk factor underlying photoaging and photocarcinogenesis. Mounting research has focused on the role of DNA damage response pathways in UV-induced double-strand break (DSB) repair. In the present study, we hypothesized that UVA-induced aberrant progerin upregulation may adversely affect p53-binding protein 1 (53BP1)-mediated non-homologous end joining (NHE) DSB repair in human keratinocytes. Basal cell carcinoma (BCC) tumors and matching normal skin tissue were sampled (n=200) to investigate whether human keratinocytes display dysregulated progerin expression as a function of advancing age and BCC status...
April 26, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28494568/-the-research-advances-and-applications-of-genome-editing-in-hereditary-eye-diseases
#10
S W Cai, Y Zhang, M Z Hou, Y Liu, X R Li
Genome editing is a cutting-edge technology that generates DNA double strand breaks at the specific genomic DNA sequence through nuclease recognition and cleavage, and then achieves insertion, replacement, or deletion of the target gene via endogenous DNA repair mechanisms, such as non-homologous end joining, homology directed repair, and homologous recombination. So far, more than 600 human hereditary eye diseases and systemic hereditary diseases with ocular phenotypes have been found. However, most of these diseases are of incompletely elucidated pathogenesis and without effective therapies...
May 11, 2017: [Zhonghua Yan Ke za Zhi] Chinese Journal of Ophthalmology
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
#11
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/28477130/monitoring-dna-repair-consequences-of-atm-signaling-using-simultaneous-fluorescent-readouts
#12
Adrian Wiegmans
The repair of deleterious DNA double strand breaks is required to maintain genome integrity. The efficacy in which this occurs relies upon the available machinery and is guided by factors that include cell cycle status, availability of donor template, and the local chromosome structure. Therefore at a single DNA breakpoint there are different outcomes that can occur. The Traffic light reporter (TLR) assay protocol is a dual fluorescent readout that has the ability to monitor simultaneous homologous recombination and non-homologous end joining activity in response to DNA damage...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28471392/taking-a-bad-turn-compromised-dna-damage-response-in-leukemia
#13
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/28460465/functional-characterisation-of-a-novel-ovarian-cancer-cell-line-nuoc-1
#14
Aiste McCormick, Eleanor Earp, Katherine Elliot, Gavin Cuthbert, Rachel O'Donnell, Brian T Wilson, Ruth Sutton, Charlotte Leeson, Huw D Thomas, Helen Blair, Sarah Fordham, John Lunec, James Allan, Richard J Edmondson
BACKGROUND: Cell lines provide a powerful model to study cancer and here we describe a new spontaneously immortalised epithelial ovarian cancer cell line (NUOC-1) derived from the ascites collected at a time of primary debulking surgery for a mixed endometrioid / clear cell / High Grade Serous (HGS) histology. RESULTS: This spontaneously immortalised cell line was found to maintain morphology and epithelial markers throughout long-term culture. NUOC-1 cells grow as an adherent monolayer with a doubling time of 58 hours...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28460268/pol%C3%AE-deficiency-induces-moderate-shortening-of-p53-mouse-lifespan-and-modifies-tumor-spectrum
#15
Beatriz Escudero, Diego Herrero, Yaima Torres, Susana Cañón, Antonio Molina, Rosa M Carmona, Javier Suela, Luis Blanco, Enrique Samper, Antonio Bernad
Non-homologous end joining (NHEJ) is the main mechanism for double strand break (DSB) DNA repair. The error-prone DNA polymerase mu (Polμ) is involved in immunoglobulin variable region rearrangement and in general, NHEJ in non-lymphoid cells. Deletion of NHEJ factors in P53(-/-) mice, which are highly prone to development of T cell lymphoma, generally increases cancer incidence and shifts the tumor spectrum towards aggressive pro-B lymphoma. In contrast, Polμ deletion increased sarcoma incidence, proportionally reducing pro-B lymphoma development on the P53-deficient background...
April 10, 2017: DNA Repair
https://www.readbyqxmd.com/read/28453785/structural-and-functional-characterization-of-the-pnkp-xrcc4-ligiv-dna-repair-complex
#16
R Daniel Aceytuno, Cortt G Piett, Zahra Havali-Shahriari, Ross A Edwards, Martial Rey, Ruiqiong Ye, Fatima Javed, Shujuan Fang, Rajam Mani, Michael Weinfeld, Michal Hammel, John A Tainer, David C Schriemer, Susan P Lees-Miller, J N Mark Glover
Non-homologous end joining (NHEJ) repairs DNA double strand breaks in non-cycling eukaryotic cells. NHEJ relies on polynucleotide kinase/phosphatase (PNKP), which generates 5΄-phosphate/3΄-hydroxyl DNA termini that are critical for ligation by the NHEJ DNA ligase, LigIV. PNKP and LigIV require the NHEJ scaffolding protein, XRCC4. The PNKP FHA domain binds to the CK2-phosphorylated XRCC4 C-terminal tail, while LigIV uses its tandem BRCT repeats to bind the XRCC4 coiled-coil. Yet, the assembled PNKP-XRCC4-LigIV complex remains uncharacterized...
April 27, 2017: Nucleic Acids Research
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/28451378/plant-genome-editing-with-talen-and-crispr
#18
REVIEW
Aimee Malzahn, Levi Lowder, Yiping Qi
Genome editing promises giant leaps forward in advancing biotechnology, agriculture, and basic research. The process relies on the use of sequence specific nucleases (SSNs) to make DNA double stranded breaks at user defined genomic loci, which are subsequently repaired by two main DNA repair pathways: non-homologous end joining (NHEJ) and homology directed repair (HDR). NHEJ can result in frameshift mutations that often create genetic knockouts. These knockout lines are useful for functional and reverse genetic studies but also have applications in agriculture...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28450160/a-novel-histone-deacetylase-inhibitor-tmu-35435-enhances-etoposide-cytotoxicity-through-the-proteasomal-degradation-of-dna-pkcs-in-triple-negative-breast-cancer
#19
Yuan-Hua Wu, Chi-Wei Hong, Yi-Ching Wang, Wei-Jan Huang, Ya-Ling Yeh, Bour-Jr Wang, Ying-Jan Wang, Hui-Wen Chiu
Triple-negative breast cancer (TNBC) treatment offers only limited benefits, and it is very relevant given the significant number of deaths that it causes. DNA repair pathways can enable tumor cells to survive DNA damage that is induced by chemotherapeutic or radiation treatments. Histone deacetylase inhibitors (HDACi) inhibited DNA repair proteins. However, the detailed mechanisms for this inhibition remain unclear. In the present study, we investigated whether a newly developed HDACi, TMU-35435, could enhance etoposide cytotoxicity by inhibiting DNA repair proteins in triple-negative breast cancer...
April 25, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28448034/using-a-fluorescent-pcr-capillary-gel-electrophoresis-technique-to-genotype-crispr-cas9-mediated-knockout-mutants-in-a-high-throughput-format
#20
Muhammad Khairul Ramlee, Jing Wang, Alice M S Cheung, Shang Li
The development of programmable genome-editing tools has facilitated the use of reverse genetics to understand the roles specific genomic sequences play in the functioning of cells and whole organisms. This cause has been tremendously aided by the recent introduction of the CRISPR/Cas9 system-a versatile tool that allows researchers to manipulate the genome and transcriptome in order to, among other things, knock out, knock down, or knock in genes in a targeted manner. For the purpose of knocking out a gene, CRISPR/Cas9-mediated double-strand breaks recruit the non-homologous end-joining DNA repair pathway to introduce the frameshift-causing insertion or deletion of nucleotides at the break site...
April 8, 2017: Journal of Visualized Experiments: JoVE
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