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Nonhomologous end joining

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https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#1
Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Grazyna Hoser, Silvia Maifrede, Esteban Martinez, Daniela Di Marcantonio, Elisabeth Bolton-Gillespie, Kimberly Cramer-Morales, Jaewong Lee, Min Li, Artur Slupianek, Daniel Gritsyuk, Sabine Cerny-Reiterer, Ilona Seferynska, Tomasz Stoklosa, Lars Bullinger, Huaqing Zhao, Vera Gorbunova, Katarzyna Piwocka, Peter Valent, Curt I Civin, Markus Muschen, John E Dick, Jean C Y Wang, Smita Bhatia, Ravi Bhatia, Kolia Eppert, Mark D Minden, Stephen M Sykes, Tomasz Skorski
Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28447610/parp3-is-a-promoter-of-chromosomal-rearrangements-and-limits-g4-dna
#2
Tovah A Day, Jacob V Layer, J Patrick Cleary, Srijoy Guha, Kristen E Stevenson, Trevor Tivey, Sunhee Kim, Anna C Schinzel, Francesca Izzo, John Doench, David E Root, William C Hahn, Brendan D Price, David M Weinstock
Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. Here we develop a zinc-finger nuclease translocation reporter and screen for factors that modulate rearrangements in human cells. We identify UBC9 and RAD50 as suppressors and 53BP1, DDB1 and poly(ADP)ribose polymerase 3 (PARP3) as promoters of chromosomal rearrangements across human cell types. We focus on PARP3 as it is dispensable for murine viability and has druggable catalytic activity...
April 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28445939/epigenetic-therapy-with-inhibitors-of-histone-methylation-suppresses-dna-damage-signaling-and-increases-glioma-cell-radiosensitivity
#3
Ozge Gursoy-Yuzugullu, Chelsea Carman, Rodolfo Bortolozo Serafim, Marios Myronakis, Valeria Valente, Brendan D Price
Radiation therapy is widely used to treat human malignancies, but many tumor types, including gliomas, exhibit significant radioresistance. Radiation therapy creates DNA double-strand breaks (DSBs), and DSB repair is linked to rapid changes in epigenetic modifications, including increased histone methylation. This increased histone methylation recruits DNA repair proteins which can then alter the local chromatin structure and promote repair. Consequently, combining inhibitors of specific histone methyltransferases with radiation therapy may increase tumor radiosensitivity, particularly in tumors with significant therapeutic resistance...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28439853/crispr-cas-mediated-in-planta-gene-targeting
#4
Simon Schiml, Friedrich Fauser, Holger Puchta
The recent emergence of the CRISPR/Cas system has boosted the possibilities for precise genome engineering approaches throughout all kingdoms of life. The most common application for plants is targeted mutagenesis, whereby a Cas9-mediated DNA double-strand break (DSB) is repaired by mutagenic nonhomologous end joining (NHEJ). However, the site-specific alteration of a genomic sequence or integration of a transgene relies on the precise repair by homologous recombination (HR) using a suitable donor sequence: this poses a particular challenge in plants, as NHEJ is the preferred repair mechanism for DSBs in somatic tissue...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28436335/localization-of-the-werner-protein-together-with-h2ax-in-%C3%AE-irradiation-induced-neoplastic-transformed-human-mesenchymal-stem-cells
#5
Nedime Serakinci, Tufan Cankaya, Steen Kølvraa
The H2A histone family, member X (H2AX), and Werner (WRN) are important proteins for genome and telomere maintenance. WRN has a major role in genome stability, particularly during DNA replication, transcription, recombination, and repair of DNA double-stranded breaks (DSBs) via base excision repair, homologous recombination, or nonhomologous end joining. H2AX plays a part in the rapid, sensitive, cellular response to the ionizing radiation or DNA-damaging chemotherapeutic agents that cause DSBs. This occurs when radiation-induced DSBs trigger the activation of H2AX and begin the damage-repair process...
2017: Critical Reviews in Eukaryotic Gene Expression
https://www.readbyqxmd.com/read/28435892/dramatic-improvement-of-crispr-cas9-editing-in-candida-albicans-by-increased-single-guide-rna-expression
#6
Henry Ng, Neta Dean
The clustered regularly interspaced short palindromic repeat system with CRISPR-associated protein 9 nuclease (CRISPR/Cas9) has emerged as a versatile tool for genome editing in Candida albicans. Mounting evidence from other model systems suggests that the intracellular levels of single guide RNA (sgRNA) limit the efficiency of Cas9-dependent DNA cleavage. Here, we tested this idea and describe a new means of sgRNA delivery that improves previously described methods by ~10-fold. The efficiency of Cas9/sgRNA-dependent cleavage and repair of a single-copy yeast enhanced monomeric red fluorescent protein (RFP) gene was measured as a function of various parameters that are hypothesized to affect sgRNA accumulation, including transcriptional and posttranscriptional processing...
March 2017: MSphere
https://www.readbyqxmd.com/read/28431013/dna-double-strand-break-repair-in-penaeus-monodon-is-predominantly-dependent-on-homologous-recombination
#7
Shikha Srivastava, Sumedha Dahal, Sharanya J Naidu, Deepika Anand, Vidya Gopalakrishnan, Rajendran Kooloth Valappil, Sathees C Raghavan
DNA double-strand breaks (DSBs) are mostly repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR) in higher eukaryotes. In contrast, HR-mediated DSB repair is the major double-strand break repair pathway in lower order organisms such as bacteria and yeast. Penaeus monodon, commonly known as black tiger shrimp, is one of the economically important crustaceans facing large-scale mortality due to exposure to infectious diseases. The animals can also get exposed to chemical mutagens under the culture conditions as well as in wild...
April 1, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/28417998/marker-free-coselection-for-crispr-driven-genome-editing-in-human-cells
#8
Daniel Agudelo, Alexis Duringer, Lusiné Bozoyan, Caroline C Huard, Sophie Carter, Jeremy Loehr, Dafni Synodinou, Mathieu Drouin, Jayme Salsman, Graham Dellaire, Josée Laganière, Yannick Doyon
Targeted genome editing enables the creation of bona fide cellular models for biological research and may be applied to human cell-based therapies. Therefore, broadly applicable and versatile methods for increasing its efficacy in cell populations are highly desirable. We designed a simple and robust coselection strategy for enrichment of cells with either nuclease-driven nonhomologous end joining (NHEJ) or homology-directed repair (HDR) events by harnessing the multiplexing capabilities of CRISPR-Cas9 and Cpf1 systems...
April 17, 2017: Nature Methods
https://www.readbyqxmd.com/read/28359030/increase-of-dna-damage-and-alteration-of-the-dna-damage-response-in-myelodysplastic-syndromes-and-acute-myeloid-leukemias
#9
Henning D Popp, Nicole Naumann, Susanne Brendel, Thomas Henzler, Christel Weiss, Wolf-Karsten Hofmann, Alice Fabarius
Increased DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability presumably implicated in pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We used immunofluorescence staining of γH2AX and 53BP1 for analyzing DNA double-strand breaks (DSB) in MDS and AML cell lines, in CD34+ selected cells of normal and MDS bone marrow (including three cases of chronic myelomonocytic leukemias) and in blasts of AML bone marrow. In addition, we screened for activation of the DDR by immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53...
March 21, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28325870/crispr-cas9-guided-oncogenic-chromosomal-translocations-with-conditional-fusion-protein-expression-in-human-mesenchymal-cells
#10
Fabio Vanoli, Mark Tomishima, Weiran Feng, Khadija Lamribet, Loelia Babin, Erika Brunet, Maria Jasin
Gene editing techniques have been extensively used to attempt to model recurrent genomic rearrangements found in tumor cells. These methods involve the induction of double-strand breaks at endogenous loci followed by the identification of breakpoint junctions within a population, which typically arise by nonhomologous end joining. The low frequency of these events, however, has hindered the cloning of cells with the desired rearrangement before oncogenic transformation. Here we present a strategy combining CRISPR-Cas9 technology and homology-directed repair to allow for the selection of human mesenchymal stem cells harboring the oncogenic translocation EWSR1-WT1 found in the aggressive desmoplastic small round cell tumor...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28324504/cytogenetic-analysis-of-telomere-dysfunction
#11
Rekha Rai, Asha S Multani, Sandy Chang
Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by the removal of telomere-binding proteins are recognized as double-stranded breaks (DSBs). Repair of DSBs is crucial for the maintenance of genome stability. In mammals, DSBs are repaired by either error-prone nonhomologous end joining (NHEJ) or error-free homologous recombination (HR) and can be visualized as chromosomal fusions.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28289912/production-of-%C3%AE-carotene-by-expressing-a-heterologous-multifunctional-carotene-synthase-in-yarrowia-lipolytica
#12
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/28265068/cas9-mediated-genome-editing-in-the-methanogenic-archaeon-methanosarcina-acetivorans
#13
Dipti D Nayak, William W Metcalf
Although Cas9-mediated genome editing has proven to be a powerful genetic tool in eukaryotes, its application in Bacteria has been limited because of inefficient targeting or repair; and its application to Archaea has yet to be reported. Here we describe the development of a Cas9-mediated genome-editing tool that allows facile genetic manipulation of the slow-growing methanogenic archaeon Methanosarcina acetivorans Introduction of both insertions and deletions by homology-directed repair was remarkably efficient and precise, occurring at a frequency of approximately 20% relative to the transformation efficiency, with the desired mutation being found in essentially all transformants examined...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28253503/xp22-31-microdeletion-due-to-microhomology-mediated-break-induced-replication-in-a-boy-with-contiguous-gene-deletion-syndrome
#14
Koki Nagai, Hirohito Shima, Miki Kamimura, Junko Kanno, Erina Suzuki, Akira Ishiguro, Satoshi Narumi, Shigeo Kure, Ikuma Fujiwara, Maki Fukami
The Xp22.31 region is characterized by a low frequency of interspersed repeats and a low GC content. Submicroscopic deletions at Xp22.31 involving STS and ANOS1 (alias KAL1) underlie X-linked ichthyosis and Kallmann syndrome, respectively. Of the known microdeletions at Xp22.31, a common approximately 1.5-Mb deletion encompassing STS was ascribed to nonallelic homologous recombination, while 2 ANOS1-containing deletions were attributed to nonhomologous end-joining. However, the genomic bases of other microdeletions within the Xp22...
2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28245065/deletion-bias-in-dna-double-strand-break-repair-differentially-contributes-to-plant-genome-shrinkage
#15
Giang T H Vu, Hieu X Cao, Bernd Reiss, Ingo Schubert
In order to prevent genome instability, cells need to be protected by a number of repair mechanisms, including DNA double-strand break (DSB) repair. The extent to which DSB repair, biased towards deletions or insertions, contributes to evolutionary diversification of genome size is still under debate. We analyzed mutation spectra in Arabidopsis thaliana and in barley (Hordeum vulgare) by PacBio sequencing of three DSB-targeted loci each, uncovering repair via gene conversion, single strand annealing (SSA) or nonhomologous end-joining (NHEJ)...
June 2017: New Phytologist
https://www.readbyqxmd.com/read/28242597/advances-in-site-specific-integration-of-transgene-in-animal-genome
#16
Li Guoling, Zhong Cuili, Mo Jianxin, Quan Rong, Wu Zhenfang, Li Zicong, Yang Huaqiang, Zhang Xianwei
The traditional transgenic technologies, such as embryo microinjection, transposon-mediated integration, or lentiviral transfection, usually result in random insertions of the foreign DNA into the host genome, which could have various disadvantages in the establishment of transgenic animals. Therefore, a strategy for site-specific integration of a transgene is needed to generate genetically modified animals with accurate and identical genotypes. However, the efficiency for site-specific integration of transgene is very low, which is mainly caused by two issues...
February 20, 2017: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/28235945/a-game-of-musical-chairs-pro-and-anti-resection-factors-compete-for-topbp1-binding-after-dna-damage
#17
Kenji Shimada, Susan M Gasser
DNA double strand breaks (DSBs) are generally repaired through nonhomologous end joining or homologous recombination. In this issue, Liu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607031) report that the conserved scaffold protein TOPBP1(Dpb11) provides binding sites for both pro- and anti-resection factors at DSBs, providing insights into repair pathway regulation.
March 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28167572/an-oncogenic-alk-fusion-and-an-rras-mutation-in-kras-mutation-negative-pancreatic-ductal-adenocarcinoma
#18
Yoko Shimada, Takashi Kohno, Hideki Ueno, Yoshinori Ino, Hideyuki Hayashi, Takashi Nakaoku, Yasunari Sakamoto, Shunsuke Kondo, Chigusa Morizane, Kazuaki Shimada, Takuji Okusaka, Nobuyoshi Hiraoka
PURPOSE: Oncogenic mutations in the KRAS gene are a well-known driver event, occurring in >95% of pancreatic cancers. The objective of this study was to identify driver oncogene aberrations in pancreatic cancers without the KRAS mutation. METHODS: Whole-exome and transcriptome sequencing was performed on four cases of KRAS mutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases. RESULTS: One case harbored an oncogenic DCTN1-ALK fusion...
February 2017: Oncologist
https://www.readbyqxmd.com/read/28159901/53bp1-contributes-to-igh-locus-chromatin-topology-during-class-switch-recombination
#19
Scott Feldman, Robert Wuerffel, Ikbel Achour, Lili Wang, Phillip B Carpenter, Amy L Kenter
In B lymphocytes, Ig class switch recombination (CSR) is induced by activation-induced cytidine deaminase, which initiates a cascade of events leading to DNA double-strand break formation in switch (S) regions. Resolution of DNA double-strand breaks proceeds through formation of S-S synaptic complexes. S-S synapsis is mediated by a chromatin loop that spans the C region domain of the Igh locus. S-S junctions are joined via a nonhomologous end joining DNA repair process. CSR occurs via an intrachromosomal looping out and deletion mechanism that is 53BP1 dependent...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28154079/dna-pkcs-structure-suggests-an-allosteric-mechanism-modulating-dna-double-strand-break-repair
#20
Bancinyane L Sibanda, Dimitri Y Chirgadze, David B Ascher, Tom L Blundell
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128-amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation...
February 3, 2017: Science
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