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https://www.readbyqxmd.com/read/28515340/turning-back-the-clock
#1
Ashley H Shoemaker
Increased DNA breaks in aging skeletal muscle activate the DNA-PK pathway, whereas blocking this pathway improves mitochondrial density, physical fitness, body weight, and insulin resistance in mice.
May 17, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28500754/mutational-phospho-mimicry-reveals-a-regulatory-role-for-the-xrcc4-and-xlf-c-terminal-tails-in-modulating-dna-bridging-during-classical-non-homologous-end-joining
#2
Davide Normanno, Aurélie Négrel, Abinadabe J de Melo, Stéphane Betzi, Katheryn Meek, Mauro Modesti
XRCC4 and DNA Ligase 4 (LIG4) form a tight complex that provides DNA ligase activity for classical non-homologous end joining (the predominant DNA double-strand break repair pathway in higher eukaryotes) and is stimulated by XLF. Independently of LIG4, XLF also associates with XRCC4 to form filaments that bridge DNA. These XRCC4/XLF complexes rapidly load and connect broken DNA, thereby stimulating intermolecular ligation. XRCC4 and XLF both include disordered C-terminal tails that are functionally dispensable in isolation but are phosphorylated in response to DNA damage by DNA-PK and/or ATM...
May 13, 2017: ELife
https://www.readbyqxmd.com/read/28482264/rational-design-synthesis-pharmacophore-modeling-and-docking-studies-for-identification-of-novel-potent-dna-pk-inhibitors
#3
Saleh Ihmaid, Hany E A Ahmed, Adeeb Al-Sheikh Ali, Yousery E Sherif, Hamadeh M Tarazi, Sayed M Riyadh, Mohamed F Zayed, Hamada S Abulkhair, Heba S Rateb
Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates...
May 2, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#4
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/28471392/taking-a-bad-turn-compromised-dna-damage-response-in-leukemia
#5
REVIEW
Nadine Nilles, Birthe Fahrenkrog
Genomic integrity is of outmost importance for the survival at the cellular and the organismal level and key to human health. To ensure the integrity of their DNA, cells have evolved maintenance programs collectively known as the DNA damage response. Particularly challenging for genome integrity are DNA double-strand breaks (DSB) and defects in their repair are often associated with human disease, including leukemia. Defective DSB repair may not only be disease-causing, but further contribute to poor treatment outcome and poor prognosis in leukemia...
May 4, 2017: Cells
https://www.readbyqxmd.com/read/28467943/beyond-making-ends-meet-dna-pk-metabolism-and-aging
#6
Xiao Tian, Andrei Seluanov, Vera Gorbunova
DNA-dependent protein kinase (DNA-PK), a central player in DNA double-strand break (DSB) repair, shows emerging roles in metabolic regulation. In this issue of Cell Metabolism, Park et al. (2017) elucidate a molecular mechanism whereby DNA-PK negatively regulates AMPK, contributing to metabolic and fitness decline during aging.
May 2, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28467930/dna-pk-promotes-the-mitochondrial-metabolic-and-physical-decline-that-occurs-during-aging
#7
Sung-Jun Park, Oksana Gavrilova, Alexandra L Brown, Jamie E Soto, Shannon Bremner, Jeonghan Kim, Xihui Xu, Shutong Yang, Jee-Hyun Um, Lauren G Koch, Steven L Britton, Richard L Lieber, Andrew Philp, Keith Baar, Steven G Kohama, E Dale Abel, Myung K Kim, Jay H Chung
Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism...
May 2, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28456783/g%C3%AE-i3-nuclear-translocation-causes-irradiation-resistance-in-human-glioma-cells
#8
Shang Cai, Ya Li, Jin-Yu Bai, Zhi-Qing Zhang, Yin Wang, Yin-Biao Qiao, Xiao-Zhong Zhou, Bo Yang, Ye Tian, C Cao
We have previously shown that Gαi3 is elevated in human glioma, mediating Akt activation and cancer cell proliferation. Here, we imply that Gαi3 could also be important for irradiation resistance. In A172 human glioma cells, Gαi3 knockdown (by targeted shRNAs) or dominant-negative mutation significantly potentiated irradiation-induced cell apoptosis. Reversely, forced over-expression of wild-type or constitutively-active Gαi3 inhibited irradiation-induced A172 cell apoptosis. Irradiation in A172 cells induced Gαi3 translocation to cell nuclei and association with local protein DNA-dependent protein kinase (DNA-PK) catalytic subunit...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28448822/hssb1-phosphorylation-is-dynamically-regulated-by-dna-pk-and-ppp-family-protein-phosphatases
#9
Nicholas W Ashton, Nicolas Paquet, Sally L Shirran, Emma Bolderson, Ruvini Kariawasam, Christine Touma, Azadeh Fallahbaghery, Roland Gamsjaeger, Liza Cubeddu, Catherine Botting, Pamela M Pollock, Kenneth J O'Byrne, Derek J Richard
The maintenance of genomic stability is essential for cellular viability and the prevention of diseases such as cancer. Human single-stranded DNA-binding protein 1 (hSSB1) is a protein with roles in the stabilisation and restart of stalled DNA replication forks, as well as in the repair of oxidative DNA lesions and double-strand DNA breaks. In the latter process, phosphorylation of threonine 117 by the ATM kinase is required for hSSB1 stability and efficient DNA repair. The regulation of hSSB1 in other DNA repair pathways has however remained unclear...
April 6, 2017: DNA Repair
https://www.readbyqxmd.com/read/28423660/progerin-impairs-vascular-smooth-muscle-cell-growth-via-the-dna-damage-response-pathway
#10
Daisuke Kinoshita, Ayako Nagasawa, Ippei Shimizu, Takashi K Ito, Yohko Yoshida, Masanori Tsuchida, Atsushi Iwama, Toshiya Hayano, Tohru Minamino
Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK)...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423228/targeting-dna-pk-for-cancer-therapy
#11
Céline Cano, Suzannah J Harnor
The catalytic activity of DNA-dependent protein kinase (DNA-PK) is critical to its ability to repair lethal DNA-double strand breaks (DSBs). This includes repair of DSB lesions resulting from oxidative stress, oncogene-induced transcription, or following therapeutic treatment of cancer cells. Armed with this knowledge, many attempts have been made to identify small molecule inhibitors of DNA-PK activity as an approach to induce tumour chemo- and radio-sensitisation. This review examines the structures of known reversible and irreversible inhibitors, including those based upon chromen-4-one, arylmorpholine, and benzaldehyde scaffolds...
April 19, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28399576/local-tumor-control-and-dna-pk-activity-of-peripheral-blood-lymphocytes-in-prostate-cancer-patients-receiving-radiotherapy
#12
Masanori Someya, Tomokazu Hasegawa, Masakazu Hori, Yoshihisa Matsumoto, Kensei Nakata, Naoya Masumori, Koh-Ichi Sakata
Repair of DNA damage is critical for genomic stability, and DNA-dependent protein kinase (DNA-PK) has an important role in repairing double-strand breaks. We examined whether the DNA-PK activity of peripheral blood lymphocytes (PBLs) was related to biochemical (prostate-specific antigen: PSA) relapse and radiation toxicity in prostate cancer patients who have received radiotherapy. A total of 69 patients with localized adenocarcinoma of the prostate participated in this study. Peripheral blood was collected 2 years or later after radiotherapy and centrifuged, then DNA-PK activity was measured by a filter binding assay...
March 1, 2017: Journal of Radiation Research
https://www.readbyqxmd.com/read/28388353/deficiency-in-dna-damage-response-a-new-characteristic-of-cells-infected-with-latent-hiv-1
#13
Dorota Piekna-Przybylska, Gaurav Sharma, Sanjay B Maggirwar, Robert A Bambara
Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells...
April 7, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28349922/coumarin-chalcone-hybrid-instigates-dna-damage-by-minor-groove-binding-and-stabilizes-p53-through-post-translational-modifications
#14
Raghib Ashraf, Hamidullah, Mohammad Hasanain, Praveen Pandey, Mayank Maheshwari, L Ravithej Singh, M Quadir Siddiqui, Rituraj Konwar, Koneni V Sashidhara, Jayanta Sarkar
S009-131, a coumarin-chalcone hybrid, had been shown to possess anti-proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA-PK, but not ATR, at earlier time points in order to initiate repair process. S009-131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28331416/dna-pk-inhibition-by-nu7441-enhances-chemosensitivity-to-topoisomerase-inhibitor-in-non-small-cell-lung-carcinoma-cells-by-blocking-dna-damage-repair
#15
Masaaki Yanai, Haruhiko Makino, Bingqiong Ping, Kenichi Takeda, Natsumi Tanaka, Tomohiro Sakamoto, Kosuke Yamaguchi, Masahiro Kodani, Akira Yamasaki, Tadashi Igishi, Eiji Shimizu
BACKGROUND: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells...
March 2017: Yonago Acta Medica
https://www.readbyqxmd.com/read/28261334/twist1-enhances-hypoxia-induced-radioresistance-in-cervical-cancer-cells-by-promoting-nuclear-egfr-localization
#16
Hua Xiong, Xin Nie, Yanmei Zou, Chen Gong, Yang Li, Hua Wu, Hong Qiu, Lin Yang, Liang Zhuang, Peng Zhang, Jing Zhang, Yihua Wang, Huihua Xiong
Twist1 is a crucial transcription factor that regulates epithelial mesenchymal transition and involves in metastasis. Recent evidence suggests that Twist1 plays important role in hypoxia-induced radioresistance, but the underlying mechanism remains elusive. Here we investigated the change of Twist1 expression in human cervical squamous cancer cell line SiHa after hypoxia treatment. We also explored the role of Twist1 in radioresistance by manipulating the expression level of Twist1. We observed that hypoxia treatment elevated the expression of Twist1 in SiHa cells...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28186989/inhibiting-dna-pkcs-in-a-non-homologous-end-joining-pathway-in-response-to-dna-double-strand-breaks
#17
Jun Dong, Tian Zhang, Yufeng Ren, Zhenyu Wang, Clifton C Ling, Fuqiu He, Gloria C Li, Chengtao Wang, Bixiu Wen
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28177883/modeling-amplified-p53-responses-under-dna-pk-inhibition-in-dna-damage-response
#18
Tingzhe Sun, Xinda Li, Pingping Shen
During DNA double strand breaks (DSBs) repair, coordinated activation of phosphatidylinositol 3-kinase (PI3K)-like kinases can activate p53 signaling pathway. Recent findings have identified novel interplays among these kinases demonstrating amplified first p53 pulses under DNA-PK inhibition. However, no theoretical model has been developed to characterize such dynamics. In current work, we modeled the prolonged p53 pulses with DNA-PK inhibitor. We could identify a dose-dependent increase in the first pulse amplitude and width...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28163277/cloning-localization-and-focus-formation-at-dna-damage-sites-of-canine-ku70
#19
Manabu Koike, Yasutomo Yutoku, Aki Koike
Understanding the molecular mechanisms of DNA double-strand break (DSB) repair machinery, specifically non-homologous DNA-end joining (NHEJ), is crucial for developing next-generation radiotherapies and common chemotherapeutics for human and animal cancers. The localization, protein-protein interactions and post-translational modifications of core NHEJ factors, might play vital roles for regulation of NHEJ activity. The human Ku heterodimer (Ku70/Ku80) is a core NHEJ factor in the NHEJ pathway and is involved in sensing of DSBs...
March 23, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/28153717/ku70-inhibits-gemcitabine-induced-dna-damage-and-pancreatic-cancer-cell-apoptosis
#20
Jiali Ma, Pingping Hui, Wenying Meng, Na Wang, Shihao Xiang
The current study focused on the role of Ku70, a DNA-dependent protein kinase (DNA-PK) complex protein, in pancreatic cancer cell resistance to gemcitabine. In both established cell lines (Mia-PaCa-2 and PANC-1) and primary human pancreatic cancer cells, shRNA/siRNA-mediated knockdown of Ku70 significantly sensitized gemcitabine-induced cell death and proliferation inhibition. Meanwhile, gemcitabine-induced DNA damage and subsequent pancreatic cancer cell apoptosis were also potentiated with Ku70 knockdown...
January 30, 2017: Biochemical and Biophysical Research Communications
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