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https://www.readbyqxmd.com/read/29144413/epstein-barr-virus-hijacks-dna-damage-response-transducers-to-orchestrate-its-life-cycle
#1
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
#2
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
#3
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 7, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29126306/the-future-of-radiobiology
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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...
October 16, 2017: DNA Repair
https://www.readbyqxmd.com/read/29074567/image-based-drug-screen-identifies-hdac-inhibitors-as-novel-golgi-disruptors-synergizing-with-jq1
#11
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
#12
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
https://www.readbyqxmd.com/read/29042365/ruxolitinib-induced-defects-in-dna-repair-cause-sensitivity-to-parp-inhibitors-in-myeloproliferative-neoplasms
#13
Margaret Nieborowska-Skorska, Silvia Maifrede, Yashodhara Dasgupta, Katherine Sullivan, Sylwia Flis, Bac Viet Le, Martyna Solecka, Elizaveta A Belyaeva, Lucia Kubovcakova, Morgan Nawrocki, Martin Kirschner, Huaqing Zhao, Josef T Prchal, Katarzyna Piwocka, Alison R Moliterno, Mariusz Wasik, Steffen Koschmieder, Tony R Green, Radek C Skoda, Tomasz Skorski
Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L) or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time primary MPN cell samples from individual patients displayed a high degree of variability in the sensitivity to these drugs...
October 17, 2017: Blood
https://www.readbyqxmd.com/read/28985363/protein-phosphatase-1-and-phosphatase-1-nuclear-targeting-subunit-dependent-regulation-of-dna-dependent-protein-kinase-and-non-homologous-end-joining
#14
Songli Zhu, Laura A Fisher, Tadayoshi Bessho, Aimin Peng
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a key role in mediating non-homologous end joining (NHEJ), a major repair pathway for DNA double-strand breaks (DSBs). The activation, function and dynamics of DNA-PKcs is regulated largely by its reversible phosphorylation at numerous residues, many of which are targeted by DNA-PKcs itself. Interestingly, these DNA-PKcs phosphorylation sites function in a distinct, and sometimes opposing manner, suggesting that they are differentially regulated via complex actions of both kinases and phosphatases...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28945226/pten-deficiency-sensitizes-endometrioid-endometrial-cancer-to-compound-parp-pi3k-inhibition-but-not-parp-inhibition-as-monotherapy
#15
X Bian, J Gao, F Luo, C Rui, T Zheng, D Wang, Y Wang, T M Roberts, P Liu, J J Zhao, H Cheng
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising cancer therapeutics especially for tumors with deficient homologous recombination (HR) repair. However, as HR-deficient tumors represent only a small fraction of endometrial cancers, the therapeutic utility of PARP inhibitors is limited in this disease. Somatic loss of phosphatase and tensin homolog (PTEN), a tumor suppressor that counteracts phosphoinositide 3-kinase (PI3K) activity, is one of the most common genetic aberrations in endometrioid endometrial cancer...
September 25, 2017: Oncogene
https://www.readbyqxmd.com/read/28923836/dna-pk-plays-a-central-role-in-transformation-of-breast-epithelial-cells-following-alkylation-damage
#16
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
#17
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/localization-of-double-strand-break-repair-proteins-to-viral-replication-compartments-following-lytic-reactivation-of-kaposi-s-sarcoma-associated-herpesvirus
#18
Robert Hollingworth, Richard D Horniblow, Calum Forrest, Grant S Stewart, Roger J Grand
Double-strand breaks (DSBs) in DNA are recognized by the Ku70/80 heterodimer and the MRE11-RAD50-NBS1 (MRN) complex and result in activation of the DNA-PK and ATM kinases, which play key roles in regulating the cellular DNA damage response (DDR). DNA tumor 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 colocalize with viral genomes in replication compartments (RCs), whereas other DSB repair proteins form foci outside RCs...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28854354/pcaf-gcn5-mediated-acetylation-of-rpa1-promotes-nucleotide-excision-repair
#19
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
#20
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
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