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Nonhomologous end joining

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https://www.readbyqxmd.com/read/28062703/tas-116-a-novel-hsp90-inhibitor-selectively-enhances-radiosensitivity-of-human-cancer-cells-to-x-rays-and-carbon-ion-radiation
#1
Younghyun Lee, Shigeaki Sunada, Hirokazu Hirakawa, Akira Fujimori, Jac A Nickoloff, Ryuichi Okayasu
Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion-irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of noncancerous human fibroblasts...
January 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28057860/contribution-of-canonical-nonhomologous-end-joining-to-chromosomal-rearrangements-is-enhanced-by-atm-kinase-deficiency
#2
Ragini Bhargava, Caree R Carson, Gabriella Lee, Jeremy M Stark
A likely mechanism of chromosomal rearrangement formation involves joining the ends from two different chromosomal double-strand breaks (DSBs). These events could potentially be mediated by either of two end-joining (EJ) repair pathways [canonical nonhomologous end joining (C-NHEJ) or alternative end joining (ALT-EJ)], which cause distinct rearrangement junction patterns. The relative role of these EJ pathways during rearrangement formation has remained controversial. Along these lines, we have tested whether the DNA damage response mediated by the Ataxia Telangiectasia Mutated (ATM) kinase may affect the relative influence of C-NHEJ vs...
January 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28030852/drug-induced-premature-senescence-model-in-human-dental-follicle-stem-cells
#3
Yuanfen Zhai, Rongbin Wei, Junjun Liu, Huihui Wang, Wenping Cai, Mengmeng Zhao, Yongguang Hu, Shuwei Wang, Tianshu Yang, Xiaodong Liu, Jianhua Yang, Shangfeng Liu
Aging is identified by a progressive decline of physiological integrity leading to age-related degenerative diseases, but its causes is unclear. Human dental pulp stem cells (hDPSCs) has a remarkable rejuvenated capacity that relies on its resident stem cells. However, because of the lack of proper senescence models, exploration of the underlying molecular mechanisms has been hindered. Here, we established a cellular model utilizing a hydroxyurea (HU) treatment protocol and effectively induced Human dental pulp stem cells to undergo cellular senescence...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27994036/microhomology-mediated-end-joining-is-activated-in-irradiated-human-cells-due-to-phosphorylation-dependent-formation-of-the-xrcc1-repair-complex
#4
Arijit Dutta, Bradley Eckelmann, Sanjay Adhikari, Kazi Mokim Ahmed, Shiladitya Sengupta, Arvind Pandey, Pavana M Hegde, Miaw-Sheue Tsai, John A Tainer, Michael Weinfeld, Muralidhar L Hegde, Sankar Mitra
Microhomology-mediated end joining (MMEJ), an error-prone pathway for DNA double-strand break (DSB) repair, is implicated in genomic rearrangement and oncogenic transformation; however, its contribution to repair of radiation-induced DSBs has not been characterized. We used recircularization of a linearized plasmid with 3'-P-blocked termini, mimicking those at X-ray-induced strand breaks, to recapitulate DSB repair via MMEJ or nonhomologous end-joining (NHEJ). Sequence analysis of the circularized plasmids allowed measurement of relative activity of MMEJ versus NHEJ...
December 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27989139/unpredicted-downregulation-of-rad51-suggests-genome-instability-induced-by-tetrachlorobenzoquinone
#5
Xiufang Song, Qiong Shi, Zixuan Liu, Yawen Wang, Yuxin Wang, Erqun Song, Yang Song
We previously demonstrated that halogenated quinone induces DNA double strand breaks (DSBs) in a ROS-dependent manner, which coordinates with downstream repair cascade including nonhomologous end joining, base excision repair, and nucleotide excision repair. However, these error-prone processes may cause the potential risk of genome instability, and current has no information on how faithful repair route, such as homologous recombination (HR), was affected. RAD51 is a key protein in the HR pathway of DSBs repair...
December 19, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27975310/a-t7-endonuclease-i-assay-to-detect-talen-mediated-targeted-mutation-of-hbv-cccdna
#6
Kristie Bloom, Abdullah Ely, Patrick Arbuthnot
Gene editing using designer nucleases is now widely used in many fields of molecular biology. The technology is being developed for the treatment of viral infections such as persistant hepatitis B virus (HBV). The replication intermediate of HBV comprising covalently closed circular DNA (cccDNA) is stable and resistant to available licensed antiviral agents. Advancing gene editing as a means of introducing targeted mutations into cccDNA thus potentially offers the means to cure infection by the virus. Essentially, targeted mutations are initiated by intracellular DNA cleavage, then error-prone nonhomologous end joining results in insertions and deletions (indels) at intended sites...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27956611/biasing-genome-editing-events-toward-precise-length-deletions-with-an-rna-guided-tevcas9-dual-nuclease
#7
Jason M Wolfs, Thomas A Hamilton, Jeremy T Lant, Marcon Laforet, Jenny Zhang, Louisa M Salemi, Gregory B Gloor, Caroline Schild-Poulter, David R Edgell
The CRISPR/Cas9 nuclease is commonly used to make gene knockouts. The blunt DNA ends generated by cleavage can be efficiently ligated by the classical nonhomologous end-joining repair pathway (c-NHEJ), regenerating the target site. This repair creates a cycle of cleavage, ligation, and target site regeneration that persists until sufficient modification of the DNA break by alternative NHEJ prevents further Cas9 cutting, generating a heterogeneous population of insertions and deletions typical of gene knockouts...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27956467/linc-complexes-promote-homologous-recombination-in-part-through-inhibition-of-nonhomologous-end-joining
#8
Katherine S Lawrence, Erin C Tapley, Victor E Cruz, Qianyan Li, Kayla Aung, Kevin C Hart, Thomas U Schwartz, Daniel A Starr, JoAnne Engebrecht
The Caenorhabditis elegans SUN domain protein, UNC-84, functions in nuclear migration and anchorage in the soma. We discovered a novel role for UNC-84 in DNA damage repair and meiotic recombination. Loss of UNC-84 leads to defects in the loading and disassembly of the recombinase RAD-51. Similar to mutations in Fanconi anemia (FA) genes, unc-84 mutants and human cells depleted of Sun-1 are sensitive to DNA cross-linking agents, and sensitivity is rescued by the inactivation of nonhomologous end joining (NHEJ)...
December 19, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27941126/evolution-of-resistance-against-crispr-cas9-gene-drive
#9
Robert L Unckless, Andrew G Clark, Philipp W Messer
CRISPR/Cas9 gene drive (CGD) promises a highly adaptable approach for spreading genetically engineered alleles throughout a species, even if those alleles impair reproductive success. CGD has been shown to be effective in laboratory crosses of insects, yet it remains unclear to what extent potential resistance mechanisms will affect the dynamics of this process in large natural populations. Here we develop a comprehensive population genetic framework for modeling CGD dynamics, which incorporates potential resistance mechanisms as well as random genetic drift...
December 10, 2016: Genetics
https://www.readbyqxmd.com/read/27924007/bridging-of-double-stranded-breaks-by-the-nonhomologous-end-joining-ligation-complex-is-modulated-by-dna-end-chemistry
#10
Dylan A Reid, Michael P Conlin, Yandong Yin, Howard H Chang, Go Watanabe, Michael R Lieber, Dale A Ramsden, Eli Rothenberg
The nonhomologous end-joining (NHEJ) pathway is the primary repair pathway for DNA double strand breaks (DSBs) in humans. Repair is mediated by a core complex of NHEJ factors that includes a ligase (DNA Ligase IV; L4) that relies on juxtaposition of 3' hydroxyl and 5' phosphate termini of the strand breaks for catalysis. However, chromosome breaks arising from biological sources often have different end chemistries, and how these different end chemistries impact the way in which the core complex directs the necessary transitions from end pairing to ligation is not known...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27924002/sfpq%C3%A2-nono-and-xlf-function-separately-and-together-to-promote-dna-double-strand-break-repair-via-canonical-nonhomologous-end-joining
#11
Lahcen Jaafar, Zhentian Li, Shuyi Li, William S Dynan
A complex of two related mammalian proteins, SFPQ and NONO, promotes DNA double-strand break repair via the canonical nonhomologous end joining (c-NHEJ) pathway. However, its mechanism of action is not fully understood. Here we describe an improved SFPQ•NONO-dependent in vitro end joining assay. We use this system to demonstrate that the SFPQ•NONO complex substitutes in vitro for the core c-NHEJ factor, XLF. Results are consistent with a model where SFPQ•NONO promotes sequence-independent pairing of DNA substrates, albeit in a way that differs in detail from XLF...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27922005/wrn-regulates-pathway-choice-between-classical-and-alternative-non-homologous-end-joining
#12
Raghavendra A Shamanna, Huiming Lu, Jessica K de Freitas, Jane Tian, Deborah L Croteau, Vilhelm A Bohr
Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27911718/attacking-hiv-1-rna-versus-dna-by-sequence-specific-approaches-rnai-versus-crispr-cas
#13
REVIEW
Elena Herrera-Carrillo, Ben Berkhout
Human immunodeficiency virus type 1 (HIV-1) infection can be effectively controlled by potent antiviral drugs, but this never results in a cure. The patient should therefore take these drugs for the rest of his/her life, which can cause drug-resistance and adverse effects. Therefore, more durable therapeutic strategies should be considered, such as a stable gene therapy to protect the target T cells against HIV-1 infection. The development of potent therapeutic regimens based on the RNA interference (RNAi) and clustered regularly interspaced short palindromic repeats (CRISPR-Cas) mechanisms will be described, which can be delivered by lentiviral vectors...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27898094/crispr-cas9-aav-mediated-knock-in-at-nrl-locus-in-human-embryonic-stem-cells
#14
Xianglian Ge, Haitao Xi, Fayu Yang, Xiao Zhi, Yanghua Fu, Ding Chen, Ren-He Xu, Ge Lin, Jia Qu, Junzhao Zhao, Feng Gu
Clustered interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome engineering technologies are sparking a new revolution in biological research. This technology efficiently induces DNA double strand breaks at the targeted genomic sequence and results in indel mutations by the error-prone process of nonhomologous end joining DNA repair or homologous recombination with a DNA repair template. The efficiency of genome editing with CRISPR/Cas9 alone in human embryonic stem cells is still low...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27895153/ubiquitylation-of-ku80-by-rnf126-promotes-completion-of-nhej-mediated-dna-repair
#15
Noriko Ishida, Tadashi Nakagawa, Shun-Ichiro Iemura, Akira Yasui, Hiroki Shima, Yasutake Katoh, Yuko Nagasawa, Toru Natsume, Kazuhiko Igarashi, Keiko Nakayama
Repair of damaged DNA is critical for maintenance of genetic information. In eukaryotes, DNA double-strand breaks (DSBs) are recognized by the Ku70-Ku80 heterodimer, which then recruits proteins that mediate repair by nonhomologous end-joining (NHEJ). Prolonged retention of Ku70/80 at DSBs prevents completion of repair, however, with ubiquitylation of Ku80 having been implicated in Ku70/80 dissociation from DNA. Here we identify RNF126 as a ubiquitin ligase that is recruited to DSBs and ubiquitylates Ku80, with UBE2D3 serving as an E2...
November 28, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27853172/lithium-promotes-dna-stability-and-survival-of-ischemic-retinal-neurocytes-by-upregulating-dna-ligase-iv
#16
Ying Yang, Nandan Wu, Sijia Tian, Fan Li, Huan Hu, Pei Chen, Xiaoxiao Cai, Lijun Xu, Jing Zhang, Zhao Chen, Jian Ge, Keming Yu, Jing Zhuang
Neurons display genomic fragility and show fragmented DNA in pathological degeneration. A failure to repair DNA breaks may result in cell death or apoptosis. Lithium protects retinal neurocytes following nutrient deprivation or partial nerve crush, but the underlying mechanisms are not well defined. Here we demonstrate that pretreatment with lithium protects retinal neurocytes from ischemia-induced damage and enhances light response in rat retina following ischemia-reperfusion injury. Moreover, we found that DNA nonhomologous end-joining (NHEJ) repair is implicated in this process because in ischemic retinal neurocytes, lithium significantly reduces the number of γ-H2AX foci (well-characterized markers of DNA double-strand breaks in situ) and increases the DNA ligase IV expression level...
November 17, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27849606/multiple-mechanisms-contribute-to-double-strand-break-repair-at-rereplication-forks-in-drosophila-follicle-cells
#17
Jessica L Alexander, Kelly Beagan, Terry L Orr-Weaver, Mitch McVey
Rereplication generates double-strand breaks (DSBs) at sites of fork collisions and causes genomic damage, including repeat instability and chromosomal aberrations. However, the primary mechanism used to repair rereplication DSBs varies across different experimental systems. In Drosophila follicle cells, developmentally regulated rereplication is used to amplify six genomic regions, two of which contain genes encoding eggshell proteins. We have exploited this system to test the roles of several DSB repair pathways during rereplication, using fork progression as a readout for DSB repair efficiency...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27798842/synthetic-lethality-between-paxx-and-xlf-in-mammalian-development
#18
Gabriel Balmus, Ana C Barros, Paul W G Wijnhoven, Chloé Lescale, Hélène Lenden Hasse, Katharina Boroviak, Carlos le Sage, Brendan Doe, Anneliese O Speak, Antonella Galli, Matt Jacobsen, Ludovic Deriano, David J Adams, Andrew N Blackford, Stephen P Jackson
PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, we generated Paxx-deficient mice. Like Xlf(-/-) mice, Paxx(-/-) mice are viable, grow normally, and are fertile but show mild radiosensitivity. Strikingly, while Paxx loss is epistatic with Ku80, Lig4, and Atm deficiency, Paxx/Xlf double-knockout mice display embryonic lethality associated with genomic instability, cell death in the central nervous system, and an almost complete block in lymphogenesis, phenotypes that closely resemble those of Xrcc4(-/-) and Lig4(-/-) mice...
October 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27788957/targeting-phosphatidylinositol-4-kinase-iii%C3%AE-for-radiosensitization-a-potential-model-of-drug-repositioning-using-an-anti-hepatitis-c-viral-agent
#19
Jeanny Kwon, Dan Hyo Kim, Ji Min Park, Young Hee Park, Yeo Hyun Hwang, Hong-Gyun Wu, Kyung Hwan Shin, In Ah Kim
PURPOSE: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells. METHODS AND MATERIALS: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed...
November 15, 2016: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/27780671/detailed-analysis-of-targeted-gene-mutations-caused-by-the-platinum-fungal-talens-in-aspergillus-oryzae-rib40-strain-and-a-ligd-disruptant
#20
Osamu Mizutani, Takayuki Arazoe, Kenji Toshida, Risa Hayashi, Shuichi Ohsato, Tetsushi Sakuma, Takashi Yamamoto, Shigeru Kuwata, Osamu Yamada
Transcription activator-like effector nucleases (TALENs), which can generate DNA double-strand breaks at specific sites in the desired genome locus, have been used in many organisms as a tool for genome editing. In Aspergilli, including Aspergillus oryzae, however, the use of TALENs has not been validated. In this study, we performed genome editing of A. oryzae wild-type strain via error of nonhomologous end-joining (NHEJ) repair by transient expression of high-efficiency Platinum-Fungal TALENs (PtFg TALENs)...
October 22, 2016: Journal of Bioscience and Bioengineering
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