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https://www.readbyqxmd.com/read/29149412/the-translationally-controlled-tumor-protein-and-the-cellular-response-to-ionizing-radiation-induced-dna-damage
#1
Jie Zhang, Grace Shim, Sonia M de Toledo, Edouard I Azzam
The absorption of ionizing radiation by living cells can directly disrupt atomic structures, producing chemical and biological changes. It can also act indirectly through radiolysis of water, thereby generating reactive chemical species that may damage nucleic acids, proteins, and lipids. Together, the direct and indirect effects of radiation initiate a series of biochemical and molecular signaling events that may repair the damage or culminate in permanent physiological changes or cell death. In efforts to gain insight into the mechanisms underlying these effects, we observed a prominent upregulation of the Translationally Controlled Tumor Protein (TCTP) in low dose/low dose rate (137)Cs γ-irradiated cells that was associated with adaptive responses that reduced chromosomal damage to a level lower than what occurs spontaneously...
2017: Results and Problems in Cell Differentiation
https://www.readbyqxmd.com/read/29133620/evaluation-of-cdk12-protein-expression-as-a-potential-novel-biomarker-for-dna-damage-response-targeted-therapies-in-breast-cancer
#2
Kalnisha Naidoo, Patty T Wai, Sarah L Maguire, Frances Daley, Syed Haider, Divya Kriplani, James Campbell, Hasan Mirza, Anita Grigoriadis, Andrew Tutt, Paul M Moseley, Tarek M A Abdel-Fatah, Stephen Yt Chan, Srinivasan Madhusudan, Emad A Rakha, Ian O Ellis, Christopher J Lord, Yinyin Yuan, Andrew R Green, Rachael Natrajan
Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29129974/screening-of-pesticides-with-the-potential-of-inducing-dsb-and-successive-recombinational-repair
#3
Karen Suárez-Larios, Ana-María Salazar-Martínez, Regina Montero-Montoya
A study was realized to ascertain whether eight selected pesticides would induce double strand breaks (DSB) in lymphocyte cultures and whether this damage would induce greater levels of proteins Rad51 participating in homologous recombination or of p-Ku80 participating in nonhomologous end joining. Only five pesticides were found to induce DSB of which only glyphosate and paraoxon induced a significant increase of p-Ku80 protein, indicating that nonhomologous end joining recombinational DNA repair system would be activated...
2017: Journal of Toxicology
https://www.readbyqxmd.com/read/29065392/cleavage-of-ku80-by-caspase-2-promotes-non-homologous-end-joining-mediated-dna-repair
#4
Qiongyu Yan, Huiqin Zhu, Li Lan, Jing Yi, Jie Yang
Non-homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks (DSBs) requires the formation of a Ku70/Ku80/DNA-PKcs complex at the DSB sites. A previous study has revealed Ku80 cleavage by caspase-3 during apoptosis. However, it remains largely unknown whether and how Ku80 cleavage affects its function in mediating NHEJ-mediated DNA repair. Here we report that Ku80 can be cleaved by caspases-2 at D726 upon a transient etoposide treatment. Caspase-2-mediated Ku80 cleavage promotes Ku80/DNA-PKcs interaction as the D726A mutation diminished Ku80 interaction with DNA-PKcs, while a Ku80 truncate (Ku80 ΔC6) lacking all the 6 residues following D726 rescued the weakened Ku80/DNA-PKcs interaction caused by caspase-2 knockdown...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29053406/super-resolution-nanoscopy-imaging-applied-to-dna-double-strand-breaks
#5
Sofia D'Abrantes, Sarah Gratton, Pamela Reynolds, Verena Kriechbaumer, Joseph McKenna, Stephen Barnard, Dave Clarke, Stanley W Botchway
Genomic deoxyribonucleic acid (DNA) is continuously being damaged by endogenous processes such as metabolism or by exogenous events such as radiation. The specific phosphorylation of histone H2AX on serine residue 139, described as γ-H2AX, is an excellent indicator or marker of DNA double-strand breaks (DSBs). The yield of γ-H2AX (foci) is shown to have some correlation with the dose of radiation or other DSB-causing agents. However, there is some discrepancy in the DNA DSB foci yield among imaging and other methods such as gel electrophoresis...
October 20, 2017: Radiation Research
https://www.readbyqxmd.com/read/28993682/olaparib-modulates-dna-repair-efficiency-sensitizes-cervical-cancer-cells-to-cisplatin-and-exhibits-anti-metastatic-property
#6
Chandra Bhushan Prasad, Shyam Babu Prasad, Suresh Singh Yadav, Laxmi Kant Pandey, Sunita Singh, Satyajit Pradhan, Gopeshwar Narayan
PARP1 trapping at DNA lesion by pharmacological inhibitors has been exploited in several cancers exhibiting defects in DNA repair mechanisms. PARP1 hyperactivation is involved in therapeutic resistance in multiple cancers. The role of PARP1 in cervical cancer (CC) resistance and implication of PARP inhibitor is yet to be elucidated. Our data demonstrates significantly higher expression of PARP1 in primary cervical tumors and CC cell lines SiHa and ME180. Upon cisplatin treatment CC cells display significant overexpression of PARP1 and its hyperactivation...
October 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28974511/tox-regulates-growth-dna-repair-and-genomic-instability-in-t-cell-acute-lymphoblastic-leukemia
#7
Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S Blackburn, Brian J Abraham, Yuka Namiki, Marc Mansour, Nouran S Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon de Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B Silverman, Ruslan I Sadreyev, John M Asara, Marjorie A Oettinger, Wilhelm Haas, A Thomas Look, Richard A Young, Raul Mostoslavsky, Graham Dellaire, David M Langenau
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection-associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair...
November 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28867292/single-molecule-imaging-reveals-how-mre11-rad50-nbs1-initiates-dna-break-repair
#8
Logan R Myler, Ignacio F Gallardo, Michael M Soniat, Rajashree A Deshpande, Xenia B Gonzalez, Yoori Kim, Tanya T Paull, Ilya J Finkelstein
DNA double-strand break (DSB) repair is essential for maintaining our genomes. Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 (Ku) direct distinct DSB repair pathways, but the interplay between these complexes at a DSB remains unclear. Here, we use high-throughput single-molecule microscopy to show that MRN searches for free DNA ends by one-dimensional facilitated diffusion, even on nucleosome-coated DNA. Rad50 binds homoduplex DNA and promotes facilitated diffusion, whereas Mre11 is required for DNA end recognition and nuclease activities...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28855246/localization-of-double-strand-break-repair-proteins-to-viral-replication-compartments-following-lytic-reactivation-of-kaposi-s-sarcoma-associated-herpesvirus
#9
Robert Hollingworth, Richard D Horniblow, Calum Forrest, Grant S Stewart, Roger J Grand
Double-strand breaks (DSBs) in DNA are recognized by the Ku70/80 heterodimer and the MRE11-RAD50-NBS1 (MRN) complex and result in activation of the DNA-PK and ATM kinases, which play key roles in regulating the cellular DNA damage response (DDR). DNA tumor viruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) are known to interact extensively with the DDR during the course of their replicative cycles. Here we show that during lytic amplification of KSHV DNA, the Ku70/80 heterodimer and the MRN complex consistently colocalize with viral genomes in replication compartments (RCs), whereas other DSB repair proteins form foci outside RCs...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28846983/indian-propolis-ameliorates-the-mitomycin-c-induced-testicular-toxicity-by-reducing-dna-damage-and-elevating-the-antioxidant-activity
#10
Sandhya Kumari, Guruprasad Nayak, Sonu T Lukose, Sneha Guruprasad Kalthur, Nandini Bhat, Aswathi R Hegde, Srinivas Mutalik, Guruprasad Kalthur, Satish Kumar Adiga
Development of excellent curative therapy for most of the malignancies has resulted in a growing population of cancer survivors who are at increased risk for a variety of health problems including infertility. Therefore, fertility preservation has become an important issue during cancer treatment in recent years. Combination therapy with natural agents such as vitamins, antioxidants, dietary supplements, and plant products are considered as an attractive option to mitigate normal tissue toxicity imparted by chemotherapy...
November 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28840859/cryo-em-structure-of-human-dna-pk-holoenzyme
#11
Xiaotong Yin, Mengjie Liu, Yuan Tian, Jiawei Wang, Yanhui Xu
DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 Å resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal α-solenoid (∼2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA...
November 2017: Cell Research
https://www.readbyqxmd.com/read/28832943/crispri-repression-of-nonhomologous-end-joining-for-enhanced-genome-engineering-via-homologous-recombination-in-yarrowia-lipolytica
#12
Cory Schwartz, Keith Frogue, Adithya Ramesh, Joshua Misa, Ian Wheeldon
In many organisms of biotechnological importance precise genome editing is limited by inherently low homologous recombination (HR) efficiencies. A number of strategies exist to increase the effectiveness of this native DNA repair pathway; however, most strategies rely on permanently disabling competing repair pathways, thus reducing an organism's capacity to repair naturally occurring double strand breaks. Here, we describe a CRISPR interference (CRISPRi) system for gene repression in the oleochemical-producing yeast Yarrowia lipolytica...
December 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28807302/targeted-overexpression-of-cyclic-amp-dependent-protein-kinase-subunit-in-toxoplasma-gondii-promotes-replication-and-virulence-in-host-cells
#13
Hongchao Sun, Suhua Wang, Xianfeng Zhao, Chaoqun Yao, Haohan Zhuang, Yechuan Huang, Xueqiu Chen, Yi Yang, Aifang Du
Toxoplasma gondii (T. gondii) is one of the most common parasite that can infect almost any warm-blooded animals including humans. The cyclic nucleotide-dependent protein kinase (PKA) regulates a spectrum of intracellular signal pathways in many organisms. Protein kinase catalytic subunit (PKAC) is the core of the whole protein, and plays an important role in the life cycle of T.gondii. Here, T.gondii PKAC (TgPKAC) overexpression strain (TgPKAC-OE) was constructed. The growth of the TgPKAC-OE, RH△Ku80, and TgPKAC inhibition strains (TgPKAC-H89) were analysed by SYBR-green real-time PCR, and the ultrastructure was observed by transmission electron microscopy...
August 30, 2017: Veterinary Parasitology
https://www.readbyqxmd.com/read/28780472/different-profiles-of-the-mrna-levels-of-dna-repair-genes-in-mcf-7-and-sh-sy5y-cells-after-treatment-with-combination-of-cisplatin-50-hz-electromagnetic-field-and-bleomycin
#14
Fatemeh Sanie-Jahromi, Mostafa Saadat
Neurotoxicity is known to be a major dose-limiting adverse effect of cisplatin (CDDP), alone or in combination with other chemicals. DNA repair capacity serve as a neuroprotective factor against CDDP. The purpose of this study was to evaluate the effect of 50-Hz electromagnetic field (EMF) in combination with CDDP and bleomycin (Bleo) on expression of some of DNA repair genes (GADD45A, XRCC1, XRCC4, Ku70, Ku80, DNA-PKcs and LIG4) in MCF-7 (breast cancer) and SH-SY5Y (neuroblastoma) cell lines. MCF-7 and SH-SY5Y cells were pre-treated with CDDP in the presence or absence of EMF and then exposed to different concentration of Bleo...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28759779/synthetic-lethality-between-murine-dna-repair-factors-xlf-and-dna-pkcs-is-rescued-by-inactivation-of-ku70
#15
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...
September 2017: DNA Repair
https://www.readbyqxmd.com/read/28717247/characterization-of-hiv-1-integrase-interaction-with-human-ku70-protein-and-initial-implications-for-drug-targeting
#16
Andrey N Anisenko, Ekaterina S Knyazhanskaya, Artur O Zalevsky, Julia Yu Agapkina, Aleksander I Sizov, Timofey S Zatsepin, Marina B Gottikh
Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with integrase from prototype foamy virus was observed. By analyzing protein subdomains we determined two binding sites in the structure of both Ku70 and integrase: the 51-160 a.a. region of integrase interacts with residues 251-438 of Ku70, whereas Ku70 N-terminal domain (1-250 a...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28712728/hexim1-and-neat1-long-non-coding-rna-form-a-multi-subunit-complex-that-regulates-dna-mediated-innate-immune-response
#17
Mehdi Morchikh, Alexandra Cribier, Raoul Raffel, Sonia Amraoui, Julien Cau, Dany Severac, Emeric Dubois, Olivier Schwartz, Yamina Bennasser, Monsef Benkirane
The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly...
August 3, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28698766/apple-flavonoids-suppress-carcinogen-induced-dna-damage-in-normal-human-bronchial-epithelial-cells
#18
Vazhappilly Cijo George, H P Vasantha Rupasinghe
SCOPE: Human neoplastic transformation due to DNA damage poses an increasing global healthcare concern. Maintaining genomic integrity is crucial for avoiding tumor initiation and progression. The present study aimed to investigate the efficacy of an apple flavonoid fraction (AF4) against various carcinogen-induced toxicity in normal human bronchial epithelial cells and its mechanism of DNA damage response and repair processes. METHODS AND RESULTS: AF4-pretreated cells were exposed to nicotine-derived nitrosamine ketones (NNK), NNK acetate (NNK-Ae), methotrexate (MTX), and cisplatin to validate cytotoxicity, total reactive oxygen species, intracellular antioxidants, DNA fragmentation, and DNA tail damage...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28668119/dna-pkcs-allostery-and-dna-double-strand-break-repair-defining-the-structure-and-setting-the-stage
#19
Dimitri Y Chirgadze, David B Ascher, Tom L Blundell, Bancinyane L Sibanda
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is central to the regulation of the DNA damage response and repair through nonhomologous end joining. The structure has proved challenging due to its large size and multiple HEAT repeats. We have recently reported crystals of selenomethionine-labeled DNA-PKcs complexed with native KU80ct194 (KU80 residues 539-732) diffracting to 4.3Å resolution. The novel use of crystals of selenomethionine-labeled protein expressed in HeLa cells has facilitated the use of single anomalous X-ray scattering of this 4128 amino acid, multiple HEAT-repeat structure...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28652322/cryo-em-structure-of-the-dna-pk-holoenzyme
#20
Humayun Sharif, Yang Li, Yuanchen Dong, Liyi Dong, Wei Li Wang, Youdong Mao, Hao Wu
DNA-dependent protein kinase (DNA-PK) is a large protein complex central to the nonhomologous end joining (NHEJ) DNA-repair pathway. It comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer of DNA-binding proteins Ku70 and Ku80. Here, we report the cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs at 4.4-Å resolution and the DNA-PK holoenzyme at 5.8-Å resolution. The DNA-PKcs structure contains three distinct segments: the N-terminal region with an arm and a bridge, the circular cradle, and the head that includes the kinase domain...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
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