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non-homologous end-joining

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https://www.readbyqxmd.com/read/28820390/small-molecule-inhibitors-of-dna-pk-for-tumor-sensitization-to-anticancer-therapy
#1
M Pospisilova, M Seifrtova, M Rezacova
The most sensitive cell structure - a DNA molecule, is the common target of cancer therapy. DNA damage response (controlled by enzymes from the phosphatidylinositol 3-kinase-related kinases family - PIKK) presents many encouraging targets for improving both conventional cytotoxic anticancer therapy and individualized monotherapy. DNA-dependent protein kinase (DNA-PK) is a member of the PIKK superfamily and plays an important role in the detection and repair of DNA double-strand breaks via the non-homologous end-joining pathway...
June 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28811466/time-lapse-crystallography-snapshots-of-a-double-strand-break-repair-polymerase-in-action
#2
Joonas A Jamsen, William A Beard, Lars C Pedersen, David D Shock, Andrea F Moon, Juno M Krahn, Katarzyna Bebenek, Thomas A Kunkel, Samuel H Wilson
DNA polymerase (pol) μ is a DNA-dependent polymerase that incorporates nucleotides during gap-filling synthesis in the non-homologous end-joining pathway of double-strand break repair. Here we report time-lapse X-ray crystallography snapshots of catalytic events during gap-filling DNA synthesis by pol μ. Unique catalytic intermediates and active site conformational changes that underlie catalysis are uncovered, and a transient third (product) metal ion is observed in the product state. The product manganese coordinates phosphate oxygens of the inserted nucleotide and PPi...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28808289/gene-editing-in-clinical-isolates-of-candida-parapsilosis-using-crispr-cas9
#3
Lisa Lombardi, Siobhán A Turner, Fang Zhao, Geraldine Butler
Candida parapsilosis is one of the most common causes of candidiasis, particularly in the very young and the very old. Studies of gene function are limited by the lack of a sexual cycle, the diploid genome, and a paucity of molecular tools. We describe here the development of a plasmid-based CRISPR-Cas9 system for gene editing in C. parapsilosis. A major advantage of the system is that it can be used in any genetic background, which we showed by editing genes in 20 different isolates. Gene editing is carried out in a single transformation step...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28801308/egfr-mutations-compromise-hypoxia-associated-radiation-resistance-through-impaired-replication-fork-associated-dna-damage-repair
#4
Mohammad Saki, Haruhiko Makino, Prashanthi Javvadi, Nozomi Tomimatsu, Lianghao Ding, Jennifer E Clark, Elaine Gavin, Kenichi Takeda, Joel Andrews, Debabrata Saha, Michael D Story, Sandeep Burma, Chaitanya Nirodi
Epidermal growth factor receptor (EGFR) signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non-small cell lung carcinomas (NSCLC) with activating L858R or ΔE746-E750 EGFR mutations exhibit elevated EGFR activity and downstream signaling. Here, relative to wild type (WT) EGFR, mutant (MT) EGFR expression significantly increases radiosensitivity in hypoxic cells. Gene expression profiling in human bronchial epithelial cells (HBEC) revealed that MT-EGFR expression elevated transcripts related to cell cycle and replication in aerobic and hypoxic conditions and down-regulated RAD50, a critical component of non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways...
August 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28794467/tdp2-suppresses-chromosomal-translocations-induced-by-dna-topoisomerase-ii-during-gene-transcription
#5
Fernando Gómez-Herreros, Guido Zagnoli-Vieira, Ioanna Ntai, María Isabel Martínez-Macías, Rhona M Anderson, Andrés Herrero-Ruíz, Keith W Caldecott
DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL...
August 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28794219/dodging-silver-bullets-good-crispr-gene-drive-design-is-critical-for-eradicating-exotic-vertebrates
#6
Thomas A A Prowse, Phillip Cassey, Joshua V Ross, Chandran Pfitzner, Talia A Wittmann, Paul Thomas
Self-replicating gene drives that can spread deleterious alleles through animal populations have been promoted as a much needed but controversial 'silver bullet' for controlling invasive alien species. Homing-based drives comprise an endonuclease and a guide RNA (gRNA) that are replicated during meiosis via homologous recombination. However, their efficacy for controlling wild populations is threatened by inherent polymorphic resistance and the creation of resistance alleles via non-homologous end-joining (NHEJ)-mediated DNA repair...
August 16, 2017: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/28791251/combining-oncolytic-adenovirus-with-radiation-a-paradigm-for-the-future-of-radiosensitization
#7
REVIEW
Sean M O'Cathail, Tzveta D Pokrovska, Timothy S Maughan, Kerry D Fisher, Leonard W Seymour, Maria A Hawkins
Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilizing quite different treatment modalities and with non-overlapping cytotoxicity profiles. It is, therefore, an intriguing possibility to consider that oncolytic ("cancer-killing") viruses may act as cancer-selective radiosensitizers, enhancing the therapeutic consequences of radiation treatment on tumors while exerting minimal effects on normal tissue. There is a solid mechanistic basis for this potential synergy, with many viruses having developed strategies to inhibit cellular DNA repair pathways in order to protect themselves, during genome replication, from unwanted interference by cell processes that are normally triggered by DNA damage...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28791037/adaptation-of-the-pivotal-differential-genome-pattern-for-the-induction-of-intergenomic-chromosome-recombination-in-hybrids-of-synthetic-amphidiploids-within-triticeae-tribe
#8
Michal T Kwiatek, Joanna Majka, Maciej Majka, Jolanta Belter, Halina Wisniewska
A pivotal-differential evolution pattern is when two allopolyploids share a common genome, which is called pivotal, and differ with respect to the other genome or genomes, called differential. This feature induces the intergenomic recombination between chromosomes of differential genomes, which can lead to speciation. Our study is a cytomolecular insight into this mechanism which was adapted for the induction of intergenomic chromosome recombination in hybrids of synthetic amphidiploids Aegilops biuncialis × S...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28781144/regulation-of-repair-pathway-choice-at-two-ended-dna-double-strand-breaks
#9
REVIEW
Atsushi Shibata
A DNA double-strand break (DSB) is considered to be a critical DNA lesion because its misrepair can cause severe mutations, such as deletions or chromosomal translocations. For the precise repair of DSBs, the repair pathway that is optimal for the particular circumstance needs to be selected. Non-homologous end joining (NHEJ) functions in G1/S/G2 phase, while homologous recombination (HR) becomes active only in S/G2 phase after DNA replication. DSB end structure is another factor affecting the repair pathway...
July 29, 2017: Mutation Research
https://www.readbyqxmd.com/read/28779875/paths-from-dna-damage-and-signaling-to-genome-rearrangements-via-homologous-recombination
#10
REVIEW
Jac A Nickoloff
DNA damage is a constant threat to genome integrity. DNA repair and damage signaling networks play a central role maintaining genome stability, suppressing tumorigenesis, and determining tumor response to common cancer chemotherapeutic agents and radiotherapy. DNA double-strand breaks (DSBs) are critical lesions induced by ionizing radiation and when replication forks encounter damage. DSBs can result in mutations and large-scale genome rearrangements reflecting mis-repair by non-homologous end joining or homologous recombination...
July 24, 2017: Mutation Research
https://www.readbyqxmd.com/read/28769923/natural-killer-cells-from-patients-with-recombinase-activating-gene-and-non-homologous-end-joining-gene-defects-comprise-a-higher-frequency-of-cd56-bright-nkg2a-cells-and-yet-display-increased-degranulation-and-higher-perforin-content
#11
Kerry Dobbs, Giovanna Tabellini, Enrica Calzoni, Ornella Patrizi, Paula Martinez, Silvia Clara Giliani, Daniele Moratto, Waleed Al-Herz, Caterina Cancrini, Morton Cowan, Jacob Bleesing, Claire Booth, David Buchbinder, Siobhan O Burns, Talal A Chatila, Janet Chou, Vanessa Daza-Cajigal, Lisa M Ott de Bruin, MaiteTeresa de la Morena, Gigliola Di Matteo, Andrea Finocchi, Raif Geha, Rakesh K Goyal, Anthony Hayward, Steven Holland, Chiung-Hui Huang, Maria G Kanariou, Alejandra King, Blanka Kaplan, Anastasiya Kleva, Taco W Kuijpers, Bee Wah Lee, Vassilios Lougaris, Michel Massaad, Isabelle Meyts, Megan Morsheimer, Benedicte Neven, Sung-Yun Pai, Alessandro Plebani, Susan Prockop, Ismail Reisli, Jian Yi Soh, Raz Somech, Troy R Torgerson, Yae-Jaen Kim, Jolan E Walter, Andrew R Gennery, Sevgi Keles, John P Manis, Emanuela Marcenaro, Alessandro Moretta, Silvia Parolini, Luigi D Notarangelo
Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag(-/-) natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28764946/balancing-act-to-be-or-not-to-be-ubiquitylated
#12
REVIEW
Ryotaro Nishi
DNA double-strand breaks (DSBs) are one of the most deleterious DNA lesions. Appropriate repair of DSB either by homologous recombination or non-homologous end-joining is critical for maintaining genome stability and fitness. DSB repair cooperates with cellular signalling networks, namely DSB response (DDR), which plays pivotal roles in the choice of DSB repair pathway, orchestrating recruitment of DDR factors to site of damage, transcription suppression and cell cycle checkpoint activation. It has been revealed that these mechanisms are strictly regulated, in time and space, by complex and minute ubiquitylation-mediated reactions...
July 21, 2017: Mutation Research
https://www.readbyqxmd.com/read/28760776/tie2-associates-with-caveolae-and-regulates-caveolin-1-to-promote-their-nuclear-translocation
#13
Mohammad B Hossain, Rehnuma Shifat, Jingyi Li, Xuemei Luo, Kenneth R Hess, Yisel Rivera-Molina, Francisco P Martinez, Hong Jiang, Frederick F Lang, Mien-Chie Hung, Juan Fueyo, Candelaria Gomez-Manzano
DNA repair pathways are aberrant in cancer, enabling tumor cells to survive standard therapies-chemotherapy and radiotherapy. Our group previously reported that, upon irradiation, the membrane-bound tyrosine kinase receptor TIE2 translocates into the nucleus and phosphorylates histone H4 at Tyr51, recruiting ABL1 to the DNA repair complexes that participate in the non-homologous end-joining pathway. However, no specific molecular mechanisms of TIE2 endocytosis have been reported. Here, we show that irradiation or ligand-induced TIE2 trafficking is dependent on caveolin-1, the main component of caveolae...
July 31, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28759779/synthetic-lethality-between-murine-dna-repair-factors-xlf-and-dna-pkcs-is-rescued-by-inactivation-of-ku70
#14
Mengtan Xing, Magnar Bjørås, Jeremy A Daniel, Frederick W Alt, Valentyn Oksenych
DNA double-strand breaks (DSBs) are recognized and repaired by the Classical Non-Homologous End-Joining (C-NHEJ) and Homologous Recombination pathways. C-NHEJ includes the core Ku70 and Ku80 (or Ku86) heterodimer that binds DSBs and thus promotes recruitment of accessory downstream NHEJ factors XLF, PAXX, DNA-PKcs, Artemis and other core subunits, XRCC4 and DNA Ligase 4 (Lig4). In the absence of core C-NHEJ factors, DNA repair can be performed by Alternative End-Joining, which likely depends on DNA Ligase 1 and DNA Ligase 3...
July 26, 2017: DNA Repair
https://www.readbyqxmd.com/read/28758991/progress-and-prospects-in-plant-genome-editing
#15
REVIEW
Kangquan Yin, Caixia Gao, Jin-Long Qiu
The emergence of sequence-specific nucleases that enable genome editing is revolutionizing basic and applied biology. Since the introduction of CRISPR-Cas9, genome editing has become widely used in transformable plants for characterizing gene function and improving traits, mainly by inducing mutations through non-homologous end joining of double-stranded breaks generated by CRISPR-Cas9. However, it would be highly desirable to perform precision gene editing in plants, especially in transformation-recalcitrant species...
July 31, 2017: Nature Plants
https://www.readbyqxmd.com/read/28754468/microhomology-mediated-end-joining-good-bad-and-ugly
#16
REVIEW
Ja-Hwan Seol, Eun Yong Shim, Sang Eun Lee
DNA double-strand breaks (DSBs) are induced by a variety of genotoxic agents, including ionizing radiation and chemotherapy drugs for treating cancers. The elimination of DSBs proceeds via distinctive error-free and error-prone pathways. Repair by homologous recombination (HR) is largely error-free and mediated by RAD51/BRCA2 gene products. Classical non-homologous end joining (C-NHEJ) requires the Ku heterodimer and can efficiently rejoin breaks, with occasional loss or gain of DNA information. Recently, evidence has unveiled another DNA end-joining mechanism that is independent of recombination factors and Ku proteins, termed alternative non-homologous end joining (A-NHEJ)...
July 16, 2017: Mutation Research
https://www.readbyqxmd.com/read/28751496/nup153-and-nup50-promote-recruitment-of-53bp1-to-dna-repair-foci-by-antagonizing-brca1-dependent-events
#17
Douglas R Mackay, Amanda C Howa, Theresa L Werner, Katharine S Ullman
DNA double strand breaks are typically repaired through either the high-fidelity process of homologous recombination (HR), in which BRCA1 plays a key role, or the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in binding to damage sites, where it protects the DNA ends from resection. The nucleoporin Nup153 has been implicated in the DNA damage response, attributed to a role in promoting nuclear import of 53BP1...
July 27, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28741662/molecular-breakdown-a-comprehensive-view-of-anaplastic-lymphoma-kinase-alk-rearranged-non-small-cell-lung-cancer
#18
Ka-Won Noh, Mi-Sook Lee, Seung Eun Lee, Ji-Young Song, Hyun-Tae Shin, Yu Jin Kim, Doo Yi Oh, Kyungsoo Jung, Minjung Sung, Mingi Kim, Sungbin An, Joungho Han, Young Mog Shim, Jae Ill Zo, Jhingook Kim, Woong-Yang Park, Se-Hoon Lee, Yoon-La Choi
Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how Echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors...
July 25, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28741180/loss-of-nhej1-protein-due-to-a-novel-splice-site-mutation-in-a-family-presenting-with-combined-immunodeficiency-microcephaly-and-growth-retardation-and-literature-review
#19
Farrukh Sheikh, Abbas Hawwari, Safa Alhissi, Sulaiman Al Gazlan, Hasan Al Dhekri, Agha M Rehan Khaliq, Esteban Borrero, Lina El-Baik, Rand Arnaout, Hamoud Al-Mousa, Anas M Alazami
INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined...
July 24, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28740167/dna-end-resection-requires-constitutive-sumoylation-of-ctip-by-cbx4
#20
Isabel Soria-Bretones, Cristina Cepeda-García, Cintia Checa-Rodriguez, Vincent Heyer, Bernardo Reina-San-Martin, Evi Soutoglou, Pablo Huertas
DNA breaks are complex DNA lesions that can be repaired by two alternative mechanisms: non-homologous end-joining and homologous recombination. The decision between them depends on the activation of the DNA resection machinery, which blocks non-homologous end-joining and stimulates recombination. On the other hand, post-translational modifications play a critical role in DNA repair. We have found that the SUMO E3 ligase CBX4 controls resection through the key factor CtIP. Indeed, CBX4 depletion impairs CtIP constitutive sumoylation and DNA end processing...
July 24, 2017: Nature Communications
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