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https://www.readbyqxmd.com/read/28641126/dna-requirements-for-interaction-of-the-c-terminal-region-of-ku80-with-the-dna-dependent-protein-kinase-catalytic-subunit-dna-pkcs
#1
Sarvan Kumar Radhakrishnan, Susan P Lees-Miller
Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks (DSBs) in human cells. Critical to NHEJ is the DNA-dependent interaction of the Ku70/80 heterodimer with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme. However, precisely how Ku recruits DNA-PKcs to DSBs ends to enhance its kinase activity has remained enigmatic, with contradictory findings reported in the literature. Here we address the role of the Ku80 C-terminal region (CTR) in the DNA-dependent interaction of Ku70/80 with DNA-PKcs using purified components and defined DNA structures...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28631426/hsp90%C3%AE-regulates-atm-and-nbn-functions-in-sensing-and-repair-of-dna-double-strand-breaks
#2
Rosa Pennisi, Antonio Antoccia, Stefano Leone, Paolo Ascenzi, Alessandra di Masi
The molecular chaperone heat shock protein 90 (Hsp90α) regulates cells proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ATM and NBN, but not 53BP1, RAD50, and MRE11, are Hsp90α clients as the Hsp90α inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cells lines...
June 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28622525/atm-atr-and-dna-pk-the-trinity-at-the-heart-of-the-dna-damage-response
#3
REVIEW
Andrew N Blackford, Stephen P Jackson
In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health...
June 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28582660/the-phytochemical-3-3-diindolylmethane-decreases-expression-of-ar-controlled-dna-damage-repair-genes-through-repressive-chromatin-modifications-and-is-associated-with-dna-damage-in-prostate-cancer-cells
#4
Zoraya Palomera-Sanchez, Gregory W Watson, Carmen P Wong, Laura M Beaver, David E Williams, Roderick H Dashwood, Emily Ho
Androgen receptor (AR) is a transcription factor involved in normal prostate physiology and prostate cancer (PCa) development. 3,3'-Diindolylmethane (DIM) is a promising phytochemical agent against PCa that affects AR activity and epigenetic regulators in PCa cells. However, whether DIM suppresses PCa via epigenetic regulation of AR target genes is unknown. We assessed epigenetic regulation of AR target genes in LNCaP PCa cells and showed that DIM treatment led to epigenetic suppression of AR target genes involved in DNA repair (PARP1, MRE11, DNA-PK)...
May 25, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28580318/targeting-ongoing-dna-damage-in-multiple-myeloma-effects-of-dna-damage-response-inhibitors-on-plasma-cell-survival
#5
Ana Belén Herrero, Norma Carmen Gutiérrez
Human myeloma cell lines (HMCLs) and a subset of myeloma patients with poor prognosis exhibit high levels of replication stress (RS), leading to DNA damage. In this study, we confirmed the presence of DNA double-strand breaks (DSBs) in several HMCLs by measuring γH2AX and RAD51 foci and analyzed the effect of various inhibitors of the DNA damage response on MM cell survival. Inhibition of ataxia telangiectasia and Rad3-related protein (ATR), the main kinase mediating the response to RS, using the specific inhibitor VE-821 induced more cell death in HMCLs than in control lymphoblastoid cells and U266, an HMCL with a low level of DNA damage...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28515340/turning-back-the-clock
#6
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
#7
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
#8
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...
June 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#9
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 Cy Wang, Smita Bhatia, Ravi Bhatia, Kolja 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...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28471392/taking-a-bad-turn-compromised-dna-damage-response-in-leukemia
#10
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
#11
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
#12
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
#13
Shang Cai, Ya Li, Jin-Yu Bai, Zhi-Qing Zhang, Yin Wang, Yin-Biao Qiao, Xiao-Zhong Zhou, Bo Yang, Ye Tian, Cong 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...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28448822/hssb1-phosphorylation-is-dynamically-regulated-by-dna-pk-and-ppp-family-protein-phosphatases
#14
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
#15
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)...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423228/targeting-dna-dependent-protein-kinase-for-cancer-therapy
#16
REVIEW
Suzannah J Harnor, Alfie Brennan, Céline Cano
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 radiosensitisation. This review examines the structures of known reversible and irreversible inhibitors, including those based on chromen-4-one, arylmorpholine, and benzaldehyde scaffolds...
June 21, 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
#17
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
#18
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...
May 19, 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
#19
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
#20
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
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