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https://www.readbyqxmd.com/read/28186989/inhibiting-dna-pkcs-in-a-non-homologous-end-joining-pathway-in-response-to-dna-double-strand-breaks
#1
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...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28177883/modeling-amplified-p53-responses-under-dna-pk-inhibition-in-dna-damage-response
#2
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...
February 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28163277/cloning-localization-and-focus-formation-at-dna-damage-sites-of-canine-ku70
#3
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...
February 6, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/28153717/ku70-inhibits-gemcitabine-induced-dna-damage-and-pancreatic-cancer-cell-apoptosis
#4
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
https://www.readbyqxmd.com/read/28139737/histone-h4-expression-is-cooperatively-maintained-by-ikk%C3%AE-and-akt1-which-attenuates-cisplatin-induced-apoptosis-through-the-dna-pk-rip1-iaps-signaling-cascade
#5
Ruixue Wang, Xuelian Zheng, Lei Zhang, Bin Zhou, Huaizhong Hu, Zhiping Li, Lin Zhang, Yong Lin, Xia Wang
While chromatin remodeling mediated by post-translational modification of histone is extensively studied in carcinogenesis and cancer cell's response to chemotherapy and radiotherapy, little is known about the role of histone expression in chemoresistance. Here we report a novel chemoresistance mechanism involving histone H4 expression. Extended from our previous studies showing that concurrent blockage of the NF-κB and Akt signaling pathways sensitizes lung cancer cells to cisplatin-induced apoptosis, we for the first time found that knockdown of Akt1 and the NF-κB-activating kinase IKKβ cooperatively downregulated histone H4 expression, which increased cisplatin-induced apoptosis in lung cancer cells...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28109743/regulation-of-human-pol%C3%AE-by-atm-mediated-phosphorylation-during-non-homologous-end-joining
#6
Guillermo Sastre-Moreno, John M Pryor, Marta Moreno-Oñate, Andrés M Herrero-Ruiz, Felipe Cortés-Ledesma, Luis Blanco, Dale A Ramsden, Jose F Ruiz
DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated...
January 17, 2017: DNA Repair
https://www.readbyqxmd.com/read/28099440/engagement-of-components-of-dna-break-repair-complex-and-nf%C3%AE%C2%BAb-in-hsp70a1a-transcription-upregulation-by-heat-shock
#7
Joyita Hazra, Pooja Mukherjee, Asif Ali, Soumita Poddar, Mahadeb Pal
An involvement of components of DNA-break repair (DBR) complex including DNA-dependent protein kinase (DNA-PK) and poly-ADP-ribose polymerase 1 (PARP-1) in transcription regulation in response to distinct cellular signalling has been revealed by different laboratories. Here, we explored the involvement of DNA-PK and PARP-1 in the heat shock induced transcription of Hsp70A1A. We find that inhibition of both the catalytic subunit of DNA-PK (DNA-PKc), and Ku70, a regulatory subunit of DNA-PK holo-enzyme compromises transcription of Hsp70A1A under heat shock treatment...
2017: PloS One
https://www.readbyqxmd.com/read/28070830/mesenchymal-subtype-of-glioblastomas-with-high-dna-pkcs-expression-is-associated-with-better-response-to-radiotherapy-and-temozolomide
#8
Baptiste Pinel, Mathilde Duchesne, Julie Godet, Serge Milin, Antoine Berger, Michel Wager, Lucie Karayan-Tapon
A better understanding of the relationship between glioblastomas molecular subtypes and radio-chemotherapy is needed for the development of individualized strategies. In this study, we aimed to assess whether non-homologous end-joining (NHEJ) protein expression is associated and could predict responses to treatment of mesenchymal (MES) and proneural (PN) subtypes. Tumors from 122 patients with a glioblastoma treated at the University Hospital of Poitiers between 2002-2013 by an association of radiotherapy and temozolomide were collected...
January 10, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28051062/paxx-promotes-ku-accumulation-at-dna-breaks-and-is-essential-for-end-joining-in-xlf-deficient-mice
#9
Xiangyu Liu, Zhengping Shao, Wenxia Jiang, Brian J Lee, Shan Zha
Non-homologous end-joining (NHEJ) is the most prominent DNA double strand break (DSB) repair pathway in mammalian cells. PAXX is the newest NHEJ factor, which shares structural similarity with known NHEJ factors-XRCC4 and XLF. Here we report that PAXX is dispensable for physiological NHEJ in otherwise wild-type mice. Yet Paxx(-/-) mice require XLF and Xlf(-/-) mice require PAXX for end-ligation. As such, Xlf(-/-)Paxx(-/-) mice display severe genomic instability and neuronal apoptosis, which eventually lead to embryonic lethality...
January 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28034453/dna-damage-repair-in-breast-cancer-and-its-therapeutic-implications
#10
REVIEW
Reem Ali, Emad A Rakha, Srinivasan Madhusudan, Helen E Bryant
The DNA damage response (DDR) involves the activation of numerous cellular activities that repair DNA lesions and maintain genomic integrity, and is critical in preventing tumorigenesis. Inherited or acquired mutations in specific genes involved in the DNA damage response, for example the breast cancer susceptibility genes 1/2 (BRCA1/2), phosphatase and tensin homolog (PTEN) and P53 are associated with various subtypes of breast cancer. Such changes can render breast cancer cells particularly sensitive to specific DNA damage response inhibitors, for example BRCA1/2 germline mutated cells are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors...
February 2017: Pathology
https://www.readbyqxmd.com/read/28011258/identification-of-kinases-phosphorylating-13-sites-in-the-nuclear-dna-binding-protein-nucks
#11
Kirsten Grundt, Bernd Thiede, Anne Carine Østvold
NUCKS is a vertebrate specific, nuclear and DNA-binding phospho protein. The protein is highly expressed in rapidly dividing cells, and is overexpressed in a number of cancer tissues. The phosphorylation of NUCKS is cell cycle and DNA-damage regulated, but little is known about the responsible kinases. By utilizing in vitro and in vivo phosphorylation assays using isolated NUCKS as well as synthetic NUCKS-derived peptides in combination with mass spectrometry, phosphopeptide mapping, phosphphoamino acid analyses, phosphospecific antibodies and the use of specific kinase inhibitors, we found that NUCKS is phosphorylated on 11 sites by CK2...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27982097/induction-of-a-cellular-dna-damage-response-by-porcine-circovirus-type-2-facilitates-viral-replication-and-mediates-apoptotic-responses
#12
Li Wei, Shanshan Zhu, Jing Wang, Rong Quan, Xu Yan, Zixue Li, Lei Hou, Naidong Wang, Yi Yang, Haijun Jiang, Jue Liu
Cellular DNA damage response (DDR) triggered by infection of DNA viruses mediate cell cycle checkpoint activation, DNA repair, or apoptosis induction. In the present study, infection of porcine circovirus type 2 (PCV2), which serves as a major etiological agent of PCV2-associated diseases (PCVAD), was found to elicit a DNA damage response (DDR) as observed by the phosphorylation of H2AX and RPA32 following infection. The response requires active viral replication, and all the ATM (ataxia telangiectasia-mutated kinase), ATR (ATM- and Rad3-related kinase), and DNA-PK (DNA-dependent protein kinase) are the transducers of the DDR signaling events in the PCV2-infected cells as demonstrated by the phosphorylation of ATM, ATR, and DNA-PK signalings as well as reductions in their activations after treatment with specific kinase inhibitors...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27935869/the-involvement-of-bcl-2-family-proteins-in-akt-regulated-cell-survival-in-cisplatin-resistant-epithelial-ovarian-cancer
#13
Yan Dai, Shiguang Jin, Xueping Li, Daxin Wang
Many studies involving patients with cisplatin-resistant ovarian cancer have shown that AKT activation leads to inhibition of apoptosis. The aim of this study was to examine the potential involvement of the Bcl-2 family proteins in AKT-regulated cell survival in response to cisplatin treatment. Cisplatin-sensitive (PEO1) and cisplatin-resistant (PEO4) cells were taken from ascites of patients with ovarian cancer before cisplatin treatment and after development of chemoresistance. It was found that cisplatin treatment activated the AKT signaling pathway and promoted cell proliferation in cisplatin-resistant EOC cells...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27887917/microrna-136-inhibits-cancer-stem-cell-activity-and-enhances-the-anti-tumor-effect-of-paclitaxel-against-chemoresistant-ovarian-cancer-cells-by-targeting-notch3
#14
Ju-Yeon Jeong, Haeyoun Kang, Tae Hoen Kim, Gwangil Kim, Jin-Hyung Heo, Ah-Young Kwon, Sewha Kim, Sang-Geun Jung, Hee-Jung An
To identify microRNAs (miRNAs) regulating Notch3 expression in association with paclitaxel resistance, candidate miRNAs targeting Notch3 were predicted using TargetScan. We found that miR-136 directly targets Notch3, and miR-136 was significantly downregulated in OSC tissues relative to normal control tissues, and low expression of miR-136 correlated with poor overall in ovarian cancer patients. Artificial miR-136 overexpression significantly reduced cell viability, proliferation, Cancer stem cell (CSC) spheroid formation, and angiogenesis, and increased apoptosis in paclitaxel-resistant SKpac cells compared with the effects of paclitaxel alone...
February 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27875301/an-intrinsically-disordered-aplf-links-ku-dna-pkcs-and-xrcc4-dna-ligase-iv-in-an-extended-flexible-non-homologous-end-joining-complex
#15
Michal Hammel, Yaping Yu, Sarvan K Radhakrishnan, Chirayu Chokshi, Miaw-Sheue Tsai, Yoshihiro Matsumoto, Monica Kuzdovich, Soumya G Remesh, Shujuan Fang, Alan E Tomkinson, Susan P Lees-Miller, John A Tainer
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). Yet, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic...
December 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27829214/pict-1-is-a-key-nucleolar-sensor-in-dna-damage-response-signaling-that-regulates-apoptosis-through-the-rpl11-mdm2-p53-pathway
#16
Hongbo Chen, Liqiao Han, Hsiangi Tsai, Zhiwei Wang, Yanping Wu, Yanhong Duo, Wei Cao, Lijun Chen, Zhirong Tan, Ning Xu, Xianzhang Huang, Junhua Zhuang, Laiqiang Huang
PICT-1 is an essential ribosome biogenesis factor whose loss induces p53 accumulation and apoptosis. Here, we show that DNA damage changes PICT-1 localization and decreases PICT-1 protein levels via the proteasome pathway. Two important phosphatidylinositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and the Ku70 subunit of DNA-dependent protein kinase (DNA-PK), co-localize and interact with PICT-1 in the nucleolus. Computational prediction of phosphorylation sites and detection using an anti-phospho-substrate antibody suggest that PICT-1 might be a substrate of PIKKs...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27813122/quercetin-alters-the-dna-damage-response-in-human-hematopoietic-stem-and-progenitor-cells-via-topoii-and-pi3k-dependent-mechanisms-synergizing-in-leukemogenic-rearrangements
#17
Shahar Biechonski, Dana Gourevich, Melanie Rall, Nasma Aqaqe, Muhammad Yassin, Adi Zipin-Roitman, Luba Trakhtenbrot, Leonid Olender, Yael Raz, Ariel J Jaffa, Dan Grisaru, Lisa Wiesmuller, David Elad, Michael Milyavsky
Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti-carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined...
February 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27776457/homologous-recombination-preferentially-repairs-heat-induced-dna-double-strand-breaks-in-mammalian-cells
#18
Akihisa Takahashi, Eiichiro Mori, Yosuke Nakagawa, Atsuhisa Kajihara, Tadaaki Kirita, L Pittman Douglas, Masatoshi Hasegawa, Takeo Ohnishi
PURPOSE: Heat shock induces DNA double-strand breaks (DSBs), but the precise mechanism of repairing heat-induced damage is unclear. Here, we investigated the DNA repair pathways involved in cell death induced by heat shock. MATERIALS AND METHODS: B02, a specific inhibitor of human RAD51 (homologous recombination; HR), and NU7026, a specific inhibitor of DNA-PK (non-homologous end-joining; NHEJ), were used for survival assays of human cancer cell lines with different p53-gene status...
October 24, 2016: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/27765510/synthesis-of-linear-and-angular-aryl-morpholino-naphth-oxazines-their-dna-pk-pi3k-pde3a-and-antiplatelet-activity
#19
Rick Morrison, Zhaohua Zheng, Ian G Jennings, Philip E Thompson, Jasim M A Al-Rawi
To continue our study of 2-morpholino-benzoxazine based compounds, which show useful activity against PI3K family enzymes or antiplatelet activity, we designed and synthesized a series of linear 6.7-fused, 5,6-angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines. The compounds were prepared from substituted 2-hydroxynaphthoic acid to give the corresponding thioxo analogues 8, 9, 15 and 19. The thioxo products were then converted to the morpholino substituted analogue. The aryl group was introduced by Suzuki coupling of bromo precursors...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27764514/sirtuins-and-their-interactions-with-transcription-factors-and-poly-adp-ribose-polymerases
#20
H Jęśko, R P Strosznajder
Sirtuins (SIRT1 to -7) are unique histone deacetylases (HDACs) whose activity depends on NAD+, thus making them capable of sensing the cellular metabolic status. Sirtuins orchestrate the stress response and damage repair, and are able to modulate the course of ageing and neurodegenerative diseases. Despite their classification as HDACs, sirtuins deacetylate a vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-B, and DNA-PK (DNA-dependent protein kinase)...
2016: Folia Neuropathologica
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