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https://www.readbyqxmd.com/read/29344644/inactivation-of-dna-pk-by-knockdown-dna-pkcs-or-nu7441-impairs-non-homologous-end-joining-of-radiation-induced-double-strand-break-repair
#1
Jun Dong, Yufeng Ren, Tian Zhang, Zhenyu Wang, Clifton C Ling, Gloria C Li, Fuqiu He, Chengtao Wang, Bixiu Wen
The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair...
January 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29287602/overcoming-hypoxia-induced-tumor-radioresistance-in-non-small-cell-lung-cancer-by-targeting-dna-dependent-protein-kinase-in-combination-with-carbon-ion-irradiation
#2
Carmen Klein, Ivana Dokic, Andrea Mairani, Stewart Mein, Stephan Brons, Peter Häring, Thomas Haberer, Oliver Jäkel, Astrid Zimmermann, Frank Zenke, Andree Blaukat, Jürgen Debus, Amir Abdollahi
BACKGROUND: Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. METHODS: Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs...
December 29, 2017: Radiation Oncology
https://www.readbyqxmd.com/read/29285139/ganoderma-lucidum-polysaccharide-enhances-radiosensitivity-of-hepatocellular-carcinoma-cell-line-hepg2-through-akt-signaling-pathway
#3
Yang Yu, Liqi Qian, Nan Du, Yuxiao Liu, Xiao Zhao, Xin Zhang
Ganoderma lucidum polysaccharide (GLP) is a well-known traditional Chinese medicine, known for its anti-cancer and immunomodulatory properties. The present study aims to investigate whether GLP has a therapeutic effect on hepatocellular carcinoma (HCC) cells exposed to radiation. Immunofluorescence was used to detect the nuclei, the protein expression was measured by western blot analysis and flow cytometry was used to detect the rate of cell apoptosis. GLP treatment was demonstrated to enhance radiation-induced growth inhibition and apoptotic death of HCC cells...
December 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29186589/detergent-insoluble-proteins-and-inclusion-body-like-structures-immunoreactive-for-prkdc-dna-pk-dna-pkcs-ftl-nnt-and-aifm1-in-the-amygdala-of-cognitively-impaired-elderly-persons
#4
Jozsef Gal, Jing Chen, Yuriko Katsumata, David W Fardo, Wang-Xia Wang, Sergey Artiushin, Douglas Price, Sonya Anderson, Ela Patel, Haining Zhu, Peter T Nelson
Misfolded protein in the amygdala is a neuropathologic feature of Alzheimer disease and many other neurodegenerative disorders. We examined extracts from human amygdala (snap-frozen at autopsy) to investigate whether novel and as yet uncharacterized misfolded proteins would be detectable. Polypeptides from the detergent-insoluble, urea-soluble protein fractions of amygdala were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. Among the detergent-insoluble proteins identified in amygdala of demented subjects but not controls were Tau, TDP-43, Aβ, α-synuclein, and ApoE...
November 24, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29179156/radiosensitization-with-an-inhibitor-of-poly-adp-ribose-glycohydrolase-a-comparison-with-the-parp1-2-3-inhibitor-olaparib
#5
Polly Gravells, James Neale, Emma Grant, Amit Nathubhai, Kate M Smith, Dominic I James, Helen E Bryant
Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize...
November 22, 2017: DNA Repair
https://www.readbyqxmd.com/read/29163809/distinct-signaling-events-promote-resistance-to-mitoxantrone-and-etoposide-in-pediatric-aml-a-children-s-oncology-group-report
#6
Xin Long, Robert B Gerbing, Todd A Alonzo, Michele S Redell
Despite aggressive chemotherapy including mitoxantrone and etoposide, relapse occurs for almost half of children with acute myeloid leukemia (AML). Since both drugs inhibit topoisomerase II and cause DNA double strand breaks, resistance could be achieved by enhanced DNA damage repair (DDR), via homologous recombination (HR) and/or non-homologous end joining (NHEJ). An important source of extrinsic chemoresistance is the bone marrow stroma. We aimed to reveal intrinsic and stroma-induced signaling pathways that contribute to chemoresistance...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163150/targeting-dna-repair-through-podophyllotoxin-and-rutin-formulation-in-hematopoietic-radioprotection-an-in-silico-in-vitro-and-in-vivo-study
#7
M H Yashavarddhan, Sandeep K Shukla, Pankaj Chaudhary, Nitya N Srivastava, Jayadev Joshi, Mrutyunjay Suar, Manju L Gupta
Drug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podophyllotoxin and rutin combination (henceforth referred as G-003M) in the hematopoietic radioprotection and its involvement in the DNA damage and repair signaling pathways. Using in silico study, we identified the binding sites and structural components of G-003M and validated in vitro...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29149412/the-translationally-controlled-tumor-protein-and-the-cellular-response-to-ionizing-radiation-induced-dna-damage
#8
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/29144413/epstein-barr-virus-hijacks-dna-damage-response-transducers-to-orchestrate-its-life-cycle
#9
REVIEW
Pok Man Hau, Sai Wah Tsao
The Epstein-Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways...
November 16, 2017: Viruses
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
#10
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/29126793/inhibition-of-notch1-hes1-signaling-pathway-improves-radiosensitivity-of-colorectal-cancer-cells
#11
Hongzhi Zhang, Huijuan Jiang, Lei Chen, Juncai Liu, Xigang Hu, Huixiang Zhang
Notch signaling pathway has been demonstrated to mediate radioresistance of several tumors. Our study aims to explore the function of Notch1/HES1 pathway in the radioresistance of colorectal cancer (CRC). The results demonstrated that expressions of Notch1 and Hes1 were up-regulated with the increasing irradiation dose. DAPT (N-[(3,5-difluorophenacetyl)acety1]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester) or si-Notch1 reduced expressions of Notch1 and Hes1, exacerbated irradiation-induced cell proliferation inhibition, and improved radiosensitivity of CRC cells...
November 8, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29126306/the-future-of-radiobiology
#12
David G Kirsch, Max Diehn, Aparna H Kesarwala, Amit Maity, Meredith A Morgan, Julie K Schwarz, Robert Bristow, Sandra Demaria, Iris Eke, Robert J Griffin, Daphne Haas-Kogan, Geoff S Higgins, Alec C Kimmelman, Randall J Kimple, Isabelle M Lombaert, Li Ma, Brian Marples, Frank Pajonk, Catherine C Park, Dörthe Schaue, Eric J Bernhard
Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors...
November 3, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29113422/novel-dna-targeted-therapies-for-head-and-neck-cancers-clinical-potential-and-biomarkers
#13
REVIEW
Mary Glorieux, Rüveyda Dok, Sandra Nuyts
Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and despite advances in treatment over the last years, there is still a relapse rate of 50%. New therapeutic agents are awaited to increase the survival of patients. DNA repair targeted agents in combination with standard DNA damaging therapies are a recent evolution in cancer treatment. These agents focus on the DNA damage repair pathways in cancer cells, which are often involved in therapeutic resistance. Interesting targets to overcome these cancer defense mechanisms are: PARP, DNA-PK, PI3K, ATM, ATR, CHK1/2, and WEE1 inhibitors...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29097284/mechanism-of-radioprotection-by-dihydroxy-1-selenolane-dhs-effect-of-fatty-acid-conjugation-and-role-of-glutathione-peroxidase-gpx
#14
Prachi Verma, Amit Kunwar, Kenta Arai, Michio Iwaoka, K Indira Priyadarsini
Dihydroxy-1-selenolane (DHS) previously reported to exhibit radioprotective activity was investigated to understand its mechanism of action in CHO cells of epithelial origin. DHS pre-treatment at 25 μM for 16 h significantly protected CHO cells from radiation (4-11 Gy)-induced delayed mitotic cell death. Further to examine, how increased cellular uptake can influence this mechanism, studies have been performed with DHS-C6, a lipophilic conjugate of DHS. Accordingly CHO cells pre-treated with DHS-C6, showed increased survival against radiation exposure...
October 30, 2017: Biochimie
https://www.readbyqxmd.com/read/29093088/polyploidy-and-mitotic-cell-death-are-two-distinct-hiv-1-vpr-driven-outcomes-in-renal-tubule-epithelial-cells
#15
Emily H Payne, Dhivya Ramalingam, Donald T Fox, Mary E Klotman
Prior studies found that HIV, through the Vpr protein, promotes genome reduplication (polyploidy) in infection-surviving epithelial cells within renal tissue. However, the temporal progression and molecular regulation through which Vpr promotes polyploidy remained unclear. Here, we define a sequential progression to Vpr-mediated polyploidy in human renal tubule epithelial cells (RTECs). As in many cell types, we find that Vpr first initiates a G2 cell cycle arrest in RTECs. We then identified a previously unreported cascade of Vpr-dependent events that lead to renal cell survival and polyploidy...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29084207/upregulation-of-the-aldoa-dna-pk-p53-pathway-by-dietary-restriction-suppresses-tumor-growth
#16
D Ma, X Chen, P-Y Zhang, H Zhang, L-J Wei, S Hu, J-Z Tang, M-T Zhou, C Xie, R Ou, Y Xu, K-F Tang
Dietary restriction (DR) delays the incidence and decreases the growth of various types of tumors; however, the mechanisms responsible for DR-mediated antitumor effects have not been unequivocally identified. Here, we report that DR suppresses xenograft tumor growth by upregulating a novel signaling pathway. DR led to upregulated aldolase A (ALDOA) expression in xenograft tumors. ALDOA physically interacted with the catalytic subunit of DNA-dependent protein kinase (DNA-PK) and promoted DNA-PK activation. Activated DNA-PK phosphorylated p53 and increased its activity...
October 30, 2017: Oncogene
https://www.readbyqxmd.com/read/29080451/curcumin-sensitizes-lymphoma-cells-to-dna-damage-agents-through-regulating-rad51-dependent-homologous-recombination
#17
Qian Zhao, Jiawei Guan, Yuanhua Qin, Peng Ren, Zhiwei Zhang, Jian Lv, Shijie Sun, Cuili Zhang, Weifeng Mao
Curcumin is a natural compound isolated from the rhizome of Curcuma longa. It possesses anti-tumor activity through arresting cell cycles and promoting cell apoptosis. However, the effect of curcumin on DNA damage is not well defined. In this study, we investigated the effect of curcumin on inducing DNA damage and on sensitizing lymphoma cells to anti-tumoral DNA damage drugs. Western blot showed curcumin induced γ-H2AX foci in CH12F3 lymphoma cells, which suggests curcumin induces DNA breaks. In addition, curcumin decreased the expression of Rad51, which suggests curcumin induces DNA damage through regulating Rad51-dependant homologous recombination...
October 25, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29078113/tdp1-is-required-for-efficient-non-homologous-end-joining-in-human-cells
#18
Jing Li, Matthew Summerlin, Karin C Nitiss, John L Nitiss, Leslyn A Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3' and 5' terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29074567/image-based-drug-screen-identifies-hdac-inhibitors-as-novel-golgi-disruptors-synergizing-with-jq1
#19
Mathieu Gendarme, Jan Baumann, Tatiana I Ignashkova, Ralph K Lindemann, Jan H Reiling
The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and is involved in numerous pathologies, including neurodegenerative diseases and cancer. The study of Golgi stress-induced signaling pathways relies on the selectivity of the available tool compounds of which currently only a few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles of cells treated with brefeldin A, golgicide A or monensin were generated and compared to a database of gene expression profiles from cells treated with other bioactive small molecules...
October 26, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29069457/nol12-is-a-multifunctional-rna-binding-protein-at-the-nexus-of-rna-and-dna-metabolism
#20
Daniel D Scott, Christian Trahan, Pierre J Zindy, Lisbeth C Aguilar, Marc Y Delubac, Eric L Van Nostrand, Srivathsan Adivarahan, Karen E Wei, Gene W Yeo, Daniel Zenklusen, Marlene Oeffinger
To counteract the breakdown of genome integrity, eukaryotic cells have developed a network of surveillance pathways to prevent and resolve DNA damage. Recent data has recognized the importance of RNA binding proteins (RBPs) in DNA damage repair (DDR) pathways. Here, we describe Nol12 as a multifunctional RBP with roles in RNA metabolism and genome maintenance. Nol12 is found in different subcellular compartments-nucleoli, where it associates with ribosomal RNA and is required for efficient separation of large and small subunit precursors at site 2; the nucleoplasm, where it co-localizes with the RNA/DNA helicase Dhx9 and paraspeckles; as well as GW/P-bodies in the cytoplasm...
October 23, 2017: Nucleic Acids Research
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