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non-homologous end joining

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https://www.readbyqxmd.com/read/27914284/applying-crispr-cas-for-genome-engineering-in-plants-the-best-is-yet-to-come
#1
REVIEW
Holger Puchta
Less than 5 years ago the CRISPR/Cas nuclease was first introduced into eukaryotes, shortly becoming the most efficient and widely used tool for genome engineering. For plants, efforts were centred on obtaining heritable changes in most transformable crop species by inducing mutations into open reading frames of interest, via non-homologous end joining. Now it is important to take the next steps and further develop the technology to reach its full potential. For breeding, besides using DNA-free editing and avoiding off target effects, it will be desirable to apply the system for the mutation of regulatory elements and for more complex genome rearrangements...
November 30, 2016: Current Opinion in Plant Biology
https://www.readbyqxmd.com/read/27905063/efficient-gene-targeting-in-mouse-zygotes-mediated-by-crispr-cas9-protein
#2
Chris J Jung, Junli Zhang, Elizabeth Trenchard, Kent C Lloyd, David B West, Barry Rosen, Pieter J de Jong
The CRISPR/Cas9 system has rapidly advanced targeted genome editing technologies. However, its efficiency in targeting with constructs in mouse zygotes via homology directed repair (HDR) remains low. Here, we systematically explored optimal parameters for targeting constructs in mouse zygotes via HDR using mouse embryonic stem cells as a model system. We characterized several parameters, including single guide RNA cleavage activity and the length and symmetry of homology arms in the construct, and we compared the targeting efficiency between Cas9, Cas9nickase, and dCas9-FokI...
November 30, 2016: Transgenic Research
https://www.readbyqxmd.com/read/27902438/dna-double-strand-break-repair-is-involved-in-desiccation-resistance-of-sinorhizobium-meliloti-but-is-not-essential-for-its-symbiotic-interaction-with-medicago-truncatula
#3
Pierre Dupuy, Benjamin Gourion, Laurent Sauviac, Claude Bruand
The soil bacterium Sinorhizobium meliloti, a nitrogen-fixing symbiont of legume plants, is exposed to numerous stress conditions in nature, some of which cause the formation of harmful DNA double strand breaks (DSB). In particular, the reactive oxygen (ROS) and nitrogen (RNS) species produced during symbiosis, and the desiccation occurring in dry soils, are conditions which induce DSB. Two major systems of DSB repair are known in S. meliloti: homologous recombination (HR) and non-homologous end-joining (NHEJ)...
November 23, 2016: Microbiology
https://www.readbyqxmd.com/read/27892716/life-and-cancer-without-telomerase-alt-and-other-strategies-for-making-sure-ends-don-t-meet
#4
Manasi S Apte, Julia Promisel Cooper
While most cancer cells rely on telomerase expression/re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10-15%) employs telomerase-independent strategies, collectively dubbed Alternative Lengthening of Telomeres (ALT). Most ALT cells relax the usual role of telomeres as inhibitors of local homologous recombination while maintaining the ability of telomeres to prohibit local non-homologous end joining reactions. Here we review current concepts surrounding how ALT telomeres achieve this new balance via alterations in chromatin landscape, DNA damage repair processes and handling of telomeric transcription...
November 28, 2016: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27883081/v-d-j-recombination-process-and-the-pre-b-to-immature-b-cells-transition-are-altered-in-fanca-mice
#5
Thuy Vy Nguyen, Patrycja Pawlikowska, Virginie Firlej, Filippo Rosselli, Saïd Aoufouchi
B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the negative selection induced by reactivity with autoantigens. Two rounds of DNA recombination are required for the production of functional immunoglobulin heavy (Ig-HCs) and light (LCs) chains necessary for the continuation of B-lymphocyte development in the BM. Both rounds depend on the joint action of recombination activating gene-1 (RAG-1) and RAG-2 endonucleases with the DNA non-homologous end-joining pathway...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27883076/a-crispr-cas9-assisted-non-homologous-end-joining-strategy-for-one-step-engineering-of-bacterial-genome
#6
Tianyuan Su, Fapeng Liu, Pengfei Gu, Haiying Jin, Yizhao Chang, Qian Wang, Quanfeng Liang, Qingsheng Qi
Homologous recombination-mediated genome engineering has been broadly applied in prokaryotes with high efficiency and accuracy. However, this method is limited in realizing larger-scale genome editing with numerous genes or large DNA fragments because of the relatively complicated procedure for DNA editing template construction. Here, we describe a CRISPR-Cas9 assisted non-homologous end-joining (CA-NHEJ) strategy for the rapid and efficient inactivation of bacterial gene (s) in a homologous recombination-independent manner and without the use of selective marker...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27875301/an-intrinsically-disordered-aplf-links-ku-dna-pkcs-and-xrcc4-dna-ligase-iv-in-an-extended-flexible-non-homologous-end-joining-complex
#7
Michal Hammel, Yaping Yu, Sarvan Kumar Radhakrishnan, Chirayu Chokshi, Miaw-Sheue Tsai, Yoshihiro Matsumoto, Monica Kuzdovich, Soumya G Remesh, Shujuan Fang, Alan E Tomkinson, Susan P Lees-Miller, John A Tainer
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF) and XRCC4 (X4)-DNA ligase IV (L4). In addition, Ku interacts with accessory factors such as Aprataxin and Polynucleotide kinase/phosphatase-Like Factor (APLF), yet how these factors interact to tether, process and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic...
November 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27869163/wwox-brca1-interaction-role-in-dna-repair-pathway-choice
#8
M S Schrock, B Batar, J Lee, T Druck, B Ferguson, J H Cho, K Akakpo, H Hagrass, N A Heerema, F Xia, J D Parvin, C M Aldaz, K Huebner
In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs)...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27869160/pot1-ob-fold-mutations-unleash-telomere-instability-to-initiate-tumorigenesis
#9
P Gu, Y Wang, K K Bisht, L Wu, L Kukova, E M Smith, Y Xiao, S M Bailey, M Lei, J Nandakumar, S Chang
Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 (POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing the activation of aberrant DNA damage and repair responses at telomeres. Sporadic and familial mutations in the oligosaccharide-oligonucleotide (OB) folds of POT1 have been identified in many human cancers, but the mechanism underlying how hPOT1 mutations initiate tumorigenesis has remained unclear...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27866150/crispr-cas9-induced-double-strand-break-repair-in-arabidopsis-non-homologous-end-joining-mutants
#10
Hexi Shen, Gary D Strunks, Bart J P M Klemann, Paul J J Hooykaas, Sylvia de Pater
Double-strand breaks (DSBs) are one of the most harmful DNA lesions. Cells utilize two main pathways for DSB repair: homologous recombination (HR) and non-homologous end-joining (NHEJ). NHEJ can be subdivided into the KU-dependent classical NHEJ (c-NHEJ) and the more error-prone KU-independent backup-NHEJ (b-NHEJ) pathways, involving the poly (ADP-ribose) polymerases (PARPs). However, in absence of these factors, cells still seem able to adequately maintain genome integrity, suggesting the presence of other b-NHEJ repair factors or pathways independent from KU and PARPs...
November 18, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27854212/non-random-distribution-of-dmd-deletion-breakpoints-and-implication-of-double-strand-breaks-repair-and-replication-error-repair-mechanisms
#11
Isabelle Marey, Rabah Ben Yaou, Nathalie Deburgrave, Aurélie Vasson, Juliette Nectoux, France Leturcq, Bruno Eymard, Pascal Laforet, Anthony Behin, Tanya Stojkovic, Michèle Mayer, Vincent Tiffreau, Isabelle Desguerre, François Constant Boyer, Aleksandra Nadaj-Pakleza, Xavier Ferrer, Karim Wahbi, Henri-Marc Becane, Mireille Claustres, Jamel Chelly, Mireille Cossee
BACKGROUND: Dystrophinopathies are mostly caused by copy number variations, especially deletions, in the dystrophin gene (DMD). Despite the large size of the gene, deletions do not occur randomly but mainly in two hot spots, the main one involving exons 45 to 55. The underlying mechanisms are complex and implicate two main mechanisms: Non-homologous end joining (NHEJ) and micro-homology mediated replication-dependent recombination (MMRDR). OBJECTIVE: Our goals were to assess the distribution of intronic breakpoints (BPs) in the genomic sequence of the main hot spot of deletions within DMD gene and to search for specific sequences at or near to BPs that might promote BP occurrence or be associated with DNA break repair...
May 27, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27853268/kin17-facilitates-multiple-double-strand-break-repair-pathways-that-govern-b-cell-class-switching
#12
Michael X Le, Dania Haddad, Alexanda K Ling, Conglei Li, Clare C So, Amit Chopra, Rui Hu, Jaime F Angulo, Jason Moffat, Alberto Martin
Class switch recombination (CSR) in B cells requires the timely repair of DNA double-stranded breaks (DSBs) that result from lesions produced by activation-induced cytidine deaminase (AID). Through a genome-wide RNAi screen, we identified Kin17 as a gene potentially involved in the maintenance of CSR in murine B cells. In this study, we confirm a critical role for Kin17 in CSR independent of AID activity. Furthermore, we make evident that DSBs generated by AID or ionizing radiation require Kin17 for efficient repair and resolution...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27849008/ku70-serine-155-mediates-aurora-b-inhibition-and-activation-of-the-dna-damage-response
#13
Victoria L Fell, Elizabeth A Walden, Sarah M Hoffer, Stephanie R Rogers, Amelia S Aitken, Louisa M Salemi, Caroline Schild-Poulter
The Ku heterodimer (Ku70/Ku80) is the central DNA binding component of the classical non-homologous end joining (NHEJ) pathway that repairs DNA double-stranded breaks (DSBs), serving as the scaffold for the formation of the NHEJ complex. Here we show that Ku70 is phosphorylated on Serine 155 in response to DNA damage. Expression of Ku70 bearing a S155 phosphomimetic substitution (Ku70 S155D) in Ku70-deficient mouse embryonic fibroblasts (MEFs) triggered cell cycle arrest at multiple checkpoints and altered expression of several cell cycle regulators in absence of DNA damage...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27836667/exploring-the-potential-of-genome-editing-crispr-cas9-technology
#14
REVIEW
Vijai Singh, Darren Braddick, Pawan Kumar Dhar
CRISPR-Cas9 is an RNA-mediated adaptive immune system that protects bacteria and archaea from viruses or plasmids. Herein we discuss the recent development of CRISPR-Cas9 into a key technology for genome editing, targeting, and regulation in a wide range of organisms and cell types. It requires a custom designed single guide-RNA (sgRNA), a Cas9 endonuclease, and PAM sequences in the target region. The sgRNA-Cas9 complex binds to its target and creates a double-strand break (DSB) that can be repaired by non-homologous end joining (NHEJ) or by the homology-directed repair (HDR) pathway, modifying or permanently replacing the genomic target sequence...
November 9, 2016: Gene
https://www.readbyqxmd.com/read/27832076/complex-breakpoints-and-template-switching-associated-with-non-canonical-termination-of-homologous-recombination-in-mammalian-cells
#15
Andrea J Hartlerode, Nicholas A Willis, Anbazhagan Rajendran, John P Manis, Ralph Scully
A proportion of homologous recombination (HR) events in mammalian cells resolve by "long tract" gene conversion, reflecting copying of several kilobases from the donor sister chromatid prior to termination. Cells lacking the major hereditary breast/ovarian cancer predisposition genes, BRCA1 or BRCA2, or certain other HR-defective cells, reveal a bias in favor of long tract gene conversion, suggesting that this aberrant HR outcome might be connected with genomic instability. If termination of gene conversion occurs in regions lacking homology with the second end of the break, the normal mechanism of HR termination by annealing (i...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27830975/deficiency-of-xlf-and-paxx-prevents-dna-double-strand-break-repair-by-non-homologous-end-joining-in-lymphocytes
#16
Putzer J Hung, Bo-Ruei Chen, Rosmy George, Caleb Liberman, Abigail J Morales, Pedro Colon-Ortiz, Jessica K Tyler, Barry P Sleckman, Andrea L Bredemeyer
Non-homologous end joining (NHEJ) is a major DNA double-strand break (DSB) repair pathway that functions in all phases of the cell cycle. NHEJ repairs genotoxic and physiological DSBs, such as those generated by ionizing radiation and during V(D)J recombination at antigen receptor loci, respectively. DNA end joining by NHEJ relies on the core factors Ku70, Ku80, XRCC4, and DNA Ligase IV. Additional proteins also play important roles in NHEJ. The XRCC4-like factor (XLF) participates in NHEJ through its interaction with XRCC4, and XLF deficiency in humans leads to immunodeficiency and increased sensitivity to ionizing radiation...
November 10, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27825805/humanku70-protein-binds-hairpin-rna-and-double-stranded-dna-through-two-different-sites
#17
Andrey N Anisenko, Ekaterina S Knyazhanskaya, Timofey S Zatsepin, Marina B Gottikh
Human protein Ku usually functions in the cell as a complex of two subunits, Ku70 and Ku80. The Ku heterodimer plays a key role in the non-homologous end joining DNA repair pathway by specifically recognizing the DNA ends at the site of the lesion. The binding of the Ku heterodimer to DNA has been well-studied, and its interactions with RNA have been also described. However, Ku70 subunit is known to have independent DNA binding capability, which is less characterized. RNA binding properties of Ku70 have not been yet specially studied...
November 4, 2016: Biochimie
https://www.readbyqxmd.com/read/27820601/scai-promotes-dna-double-strand-break-repair-in-distinct-chromosomal-contexts
#18
Rebecca Kring Hansen, Andreas Mund, Sara Lund Poulsen, Maria Sandoval, Karolin Klement, Katerina Tsouroula, Maxim A X Tollenaere, Markus Räschle, Rebeca Soria, Stefan Offermanns, Thomas Worzfeld, Robert Grosse, Dominique T Brandt, Björn Rozell, Matthias Mann, Francesca Cole, Evi Soutoglou, Aaron A Goodarzi, Jeremy A Daniel, Niels Mailand, Simon Bekker-Jensen
DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment. Here, we identify SCAI (suppressor of cancer cell invasion) as a 53BP1-interacting chromatin-associated protein that promotes the functionality of several DSB repair pathways in mammalian cells. SCAI undergoes prominent enrichment at DSB sites through dual mechanisms involving 53BP1-dependent recruitment to DSB-surrounding chromatin and 53BP1-independent accumulation at resected DSBs...
November 7, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27819301/talen-mediated-knock-in-via-non-homologous-end-joining-in-the-crustacean-daphnia-magna
#19
Takashi Nakanishi, Yasuhiko Kato, Tomoaki Matsuura, Hajime Watanabe
Transcription activator-like effector nucleases (TALENs) are versatile tools that enable the insertion of DNA into different organisms. Here, we confirmed TALEN-mediated knock-in via non-homologous end joining in the crustacean Daphnia magna, a model organism for ecological and toxicological genomics. We tested two different TALENs, ey1 TALEN and ey2 TALEN, both of which target the eyeless locus. The donor DNA plasmid, harbouring the H2B-GFP reporter gene, was designed to contain both TALEN target sites and was co-injected with each TALEN mRNA into eggs...
November 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27814655/mitochondrial-dna-repair-and-damage-tolerance
#20
Alexis Stein, Elaine A Sia
The accurate maintenance of mitochondrial DNA (mtDNA) is required in order for eukaryotic cells to assemble a functional electron transport chain. This independently-maintained genome relies on nuclear-encoded proteins that are imported into the mitochondria to carry out replication and repair processes. Decades of research has made clear that mitochondria employ robust and varied mtDNA repair and damage tolerance mechanisms in order to ensure the proper maintenance of the mitochondrial genome. This review focuses on our current understanding of mtDNA repair and damage tolerance pathways including base excision repair, mismatch repair, homologous recombination, non-homologous end joining, translesion synthesis and mtDNA degradation in both yeast and mammalian systems...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
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