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https://www.readbyqxmd.com/read/28923836/dna-pk-plays-a-central-role-in-transformation-of-breast-epithelial-cells-following-alkylation-damage
#1
Libi Anandi, Vaishali Chakravarty, K A Ashiq, Satish Bodakuntla, Mayurika Lahiri
DNA alkylating agents form the first line of cancer chemotherapy. They not only kill cells but also behave as potential carcinogens. MNU, a DNA methylating agent is well known to induce mammary tumours in rodents. However, the mechanism of tumorigenesis is not well understood. Our study reports a novel role played by DNA-PK in methylation damage-induced transformation using three dimensional breast acinar cultures. Here, we report that exposure of breast epithelial cells to MNU led to their inhibition to polarise at the basolateral domain, increased dispersal of Golgi at the apical domain, induction of EMT-like phenotype as well as invasion...
September 18, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28893936/take-your-pikk-tumour-viruses-and-dna-damage-response-pathways
#2
REVIEW
Neha J Pancholi, Alexander M Price, Matthew D Weitzman
Viruses regulate cellular processes to facilitate viral replication. Manipulation of nuclear proteins and pathways by nuclear replicating viruses often causes cellular genome instability that contributes to transformation. The cellular DNA damage response (DDR) safeguards the host to maintain genome integrity, but DNA tumour viruses can manipulate the DDR to promote viral propagation. In this review, we describe the interactions of DNA tumour viruses with the phosphatidylinositol 3-kinase-like protein kinase (PIKK) pathways, which are central regulatory arms of the DDR...
October 19, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28855246/localisation-of-double-strand-break-repair-proteins-to-viral-replication-compartments-following-lytic-reactivation-of-kshv
#3
Robert Hollingworth, Richard D Horniblow, Calum Forrest, Grant S Stewart, Roger J Grand
Double-strand breaks (DSBs) in DNA are recognised by the Ku70/80 heterodimer and the MRE11-RAD50-NBS1 (MRN) complex and result in activation of the DNA-PK and ATM kinases that play key roles in regulating the cellular DNA damage response (DDR). DNA tumour 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 co-localise with viral genomes in replication compartments (RCs) whereas other DSB repair proteins form foci outside of RCs...
August 30, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28854354/pcaf-gcn5-mediated-acetylation-of-rpa1-promotes-nucleotide-excision-repair
#4
Meimei Zhao, Rui Geng, Xiang Guo, Ruoshi Yuan, Xiao Zhou, Yanyan Zhong, Yanfei Huo, Mei Zhou, Qinjian Shen, Yinglu Li, Weiguo Zhu, Jiadong Wang
The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28851987/p53-represses-pyrimidine-catabolic-gene-dihydropyrimidine-dehydrogenase-dpyd-expression-in-response-to-thymidylate-synthase-ts-targeting
#5
Prashanth Gokare, Niklas K Finnberg, Phillip H Abbosh, Jenny Dai, Maureen E Murphy, Wafik S El-Deiry
Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28840859/cryo-em-structure-of-human-dna-pk-holoenzyme
#6
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...
August 25, 2017: Cell Research
https://www.readbyqxmd.com/read/28838830/synthesis-and-biological-evaluation-of-8-aryl-2-morpholino-7-o-substituted-benzo-e-1-3-oxazin-4-ones-against-dna-pk-pi3k-pde3a-enzymes-and-platelet-aggregation
#7
Md Saifuzzaman, Rick Morrison, Zhaohua Zheng, Stephanie Orive, Justin Hamilton, Philip E Thompson, Jasim M A Al-Rawi
A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-position. The 2 protons of 7-OCH2 in compounds 18g, 18h, 18i, 18l and 18m prove to be magnetically non-equivalent, atropisomerism (axial chirality), as result of sterically hindered rotation of the bulky 8-aryl-substituent...
August 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28837154/akt2-suppresses-pro-survival-autophagy-triggered-by-dna-double-strand-breaks-in-colorectal-cancer-cells
#8
Nina Seiwert, Carina Neitzel, Svenja Stroh, Teresa Frisan, Marc Audebert, Mahmoud Toulany, Bernd Kaina, Jörg Fahrer
DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28821159/inhibition-of-dna-pk-enhances-chemosensitivity-of-b-cell-precursor-acute-lymphoblastic-leukemia-cells-to-doxorubicin
#9
Fatemeh Alikarami, Majid Safa, Mohammad Faranoush, Parisa Hayat, Ahmad Kazemi
DNA damage repair pathways greatly affect the response to genotoxic drugs in cancer cells, so inhibition of such pathways could be a potentially useful strategy to enhance chemosensitivity. DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DNA double-strand breaks (DSBs) that are probably one of the most detrimental types of DNA damage. It has been shown that DNA-PK is highly expressed in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. Less well appreciated was the effect of DNA-PK inhibition on sensitivity of BCP-ALL cells to DNA-damaging agents...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28820390/small-molecule-inhibitors-of-dna-pk-for-tumor-sensitization-to-anticancer-therapy
#10
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/28775208/a-multikinase-and-dna-pk-inhibitor-combination-immunomodulates-melanomas-suppresses-tumor-progression-and-enhances-immunotherapies
#11
Alexander K Tsai, Asra Y Khan, Christina E Worgo, Lucy L Wang, Yuanyuan Liang, Eduardo Davila
Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib (Reg) and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death-ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and HLA class I in a heterogeneous panel of melanomas...
August 3, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28768182/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
No abstract text is available yet for this article.
August 1, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28758831/tet1-deficiency-attenuates-the-dna-damage-response-and-promotes-resistance-to-dna-damaging-agents
#13
Jonathan B Coulter, Hernando Lopez-Bertoni, Katherine J Kuhns, Richard S Lee, John Laterra, Joseph P Bressler
Recent studies have shown that loss of TET1 may play a significant role in the formation of tumors. Because genomic instability is a hallmark of cancer, we examined the potential involvement of ten-eleven translocation 1 (TET1) in the DNA damage response (DDR). Here we demonstrate that, in response to clinically relevant doses of ionizing radiation (IR), human glial cells made TET1-deficient with lentiviral vectors displayed greater numbers of colony forming units and lower levels of apoptotic markers compared to glial cells transduced with control vectors; yet, they harbored greater DNA strand breaks...
July 31, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28754673/androgen-receptor-variants-mediate-dna-repair-after-prostate-cancer-irradiation
#14
Yi Yin, Rui Li, Kangling Xu, Sentai Ding, Jeffrey Li, GuemHee Baek, Susmita G Ramanand, Sam Ding, Zhao Liu, Yunpeng Gao, Mohammed S Kanchwala, Xiangyi Li, Ryan Hutchinson, Xihui Liu, Solomon L Woldu, Chao Xing, Neil B Desai, Felix Y Feng, Sandeep Burma, Johann S de Bono, Scott M Dehm, Ram S Mani, Benjamin P C Chen, Ganesh V Raj
In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner...
September 15, 2017: Cancer Research
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
#15
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/28707218/the-dna-damage-response-pathway-in-normal-hematopoiesis-and-malignancies
#16
REVIEW
Domenico Delia, Shuki Mizutani
In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations...
July 13, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28706768/dna-pk-and-p38-mapk-a-kinase-collusion-in-alzheimer-s-disease
#17
Jyotshna Kanungo
The pathogenesis of Alzheimer's disease (AD), characterized by prevalent neuronal death and extracellular deposit of amyloid plaques, is poorly understood. DNA lesions downstream of reduced DNA repair ability have been reported in AD brains. Neurons predominantly use a mechanism to repair double-strand DNA breaks (DSB), which is non-homologous end joining (NHEJ). NHEJ requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 and p70 subunits...
2017: Brain Disorders & Therapy
https://www.readbyqxmd.com/read/28686579/synergy-between-prkdc-and-trp53-regulates-stem-cell-proliferation-and-gi-ars-after-irradiation
#18
Kay E Gurley, Amanda K Ashley, Russell D Moser, Christopher J Kemp
Ionizing radiation (IR) is one of the most widely used treatments for cancer. However, acute damage to the gastrointestinal tract or gastrointestinal acute radiation syndrome (GI-ARS) is a major dose-limiting side effect, and the mechanisms that underlie this remain unclear. Here we use mouse models to explore the relative roles of DNA repair, apoptosis, and cell cycle arrest in radiation response. IR induces DNA double strand breaks and DNA-PK mutant Prkdc(scid/scid) mice are sensitive to GI-ARS due to an inability to repair these breaks...
July 7, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28652322/cryo-em-structure-of-the-dna-pk-holoenzyme
#19
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
https://www.readbyqxmd.com/read/28645898/dna-pk-facilitates-piggybac-transposition-by-promoting-paired-end-complex-formation
#20
Yan Jin, Yaohui Chen, Shimin Zhao, Kun-Liang Guan, Yuan Zhuang, Wenhao Zhou, Xiaohui Wu, Tian Xu
The involvement of host factors is critical to our understanding of underlying mechanisms of transposition and the applications of transposon-based technologies. Modified piggyBac (PB) is one of the most potent transposon systems in mammals. However, varying transposition efficiencies of PB among different cell lines have restricted its application. We discovered that the DNA-PK complex facilitates PB transposition by binding to PB transposase (PBase) and promoting paired-end complex formation. Mass spectrometry analysis and coimmunoprecipitation revealed physical interaction between PBase and the DNA-PK components Ku70, Ku80, and DNA-PKcs Overexpression or knockdown of DNA-PK components enhances or suppresses PB transposition in tissue culture cells, respectively...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
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