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https://www.readbyqxmd.com/read/29786079/dissection-of-dna-double-strand-break-repair-using-novel-single-molecule-forceps
#1
Jing L Wang, Camille Duboc, Qian Wu, Takashi Ochi, Shikang Liang, Susan E Tsutakawa, Susan P Lees-Miller, Marc Nadal, John A Tainer, Tom L Blundell, Terence R Strick
Repairing DNA double-strand breaks (DSBs) by nonhomologous end joining (NHEJ) requires multiple proteins to recognize and bind DNA ends, process them for compatibility, and ligate them together. We constructed novel DNA substrates for single-molecule nanomanipulation, allowing us to mechanically detect, probe, and rupture in real-time DSB synapsis by specific human NHEJ components. DNA-PKcs and Ku allow DNA end synapsis on the 100 ms timescale, and the addition of PAXX extends this lifetime to ~2 s. Further addition of XRCC4, XLF and ligase IV results in minute-scale synapsis and leads to robust repair of both strands of the nanomanipulated DNA...
May 21, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29760601/tumor-cell-accelerated-senescence-is-associated-with-dna-pkcs-status-and-telomere-dysfunction-induced-by-radiation
#2
Miaomiao Zhang, Xiaopeng Guo, Yue Gao, Dong Lu, Wenjian Li
Whether telomere structure integrity is related to radiosensitivity is not well investigated thus far. In this study, we investigated the relation between telomere instability and radiation-induced accelerated senescence. Partial knockdown of DNA-dependent catalytic subunit of protein kinase (DNA-PKcs) in human breast cancer cell line MCF-7 was established by small interfering RNA. Radiosensitivity of control and DNA-PKcs knockdown MCF-7 cells was analyzed by clonogenetic assay. Cell growth was measured by real-time cell electronic sensing...
April 2018: Dose-response: a Publication of International Hormesis Society
https://www.readbyqxmd.com/read/29752438/role-of-fgfr2b-expression-and-signaling-in-keratinocyte-differentiation-sequential-involvement-of-pkc%C3%AE-and-pkc%C3%AE
#3
Benedetta Rosato, Danilo Ranieri, Monica Nanni, Maria Rosaria Torrisi, Francesca Belleudi
The tumor suppressor epithelial isoform of the fibroblast growth factor receptor 2 (FGFR2b) induces human keratinocyte early differentiation. Moreover, protein kinases C (PKCs) are known to regulate the differentiation program in several cellular contexts, including keratinocytes. Therefore, in this paper we propose to clarify if FGFR2b could play a role also in the late steps of keratinocyte differentiation and to assess if this receptor-induced process would sequentially involve PKCδ and PKCα isoforms. Immunofluorescence, biochemical, and molecular approaches, performed on 2D cultures or 3D organotypic rafts of human keratinocytes overexpressing FGFR2b by stable transduction, showed that receptor signaling induced the precocious onset and an accelerated progression of keratinocyte differentiation, indicating that FGFR2b is a crucial regulator of the entire program of keratinocyte differentiation...
May 11, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29706864/ethanol-induced-changes-in-pkc%C3%AE%C2%B5-from-cell-to-behavior
#4
REVIEW
Rashidi M Pakri Mohamed, Mohd H Mokhtar, Ernie Yap, Athirah Hanim, Norhazlina Abdul Wahab, Farah H F Jaffar, Jaya Kumar
The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCε is the most implicated in ethanol-induced biochemical and behavioral changes...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29702521/dna-damage-pathways-and-b-cell-lymphomagenesis
#5
Gero Knittel, Tim Rehkämper, Pascal Nieper, Anna Schmitt, Ruth Flümann, H Christian Reinhardt
PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity...
April 26, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29699771/propofol-induced-diverse-and-subtype-specific-translocation-of-pkc-families
#6
Takeshi Miyahara, Naoko Adachi, Takahiro Seki, Izumi Hide, Shigeru Tanaka, Naoaki Saito, Masahiro Irifune, Norio Sakai
Propofol is the most commonly used anesthetic. Immunohistochemical studies have reported that propofol translocated protein kinase Cs (PKCs) in cardiomyocyte in a subtype-specific manner; however detailed features of the propofol-induced translocation of PKCs remain unknown. In this study, we performed real-time observation of propofol-induced PKC translocation in SH-SY5Y cells expressing PKCs fused with a fluorescent protein. Propofol unidirectionally translocated γPKC-GFP, a conventional PKC, and ζPKC-GFP, an atypical PKC, to the plasma membrane and nucleus, respectively, whereas the propofol-induced translocation of novel PKCs was diverse and subtype-specific among δPKC, εPKC and ηPKC...
April 6, 2018: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29685705/genistein-sensitizes-glioblastoma-cells-to-carbon-ions-via-inhibiting-dna-pkcs-phosphorylation-and-subsequently-repressing-nhej-and-delaying-hr-repair-pathways
#7
Xiongxiong Liu, Ping Li, Ryoichi Hirayama, Yuzhen Niu, Xinguo Liu, Weiqiang Chen, Xiaodong Jin, Pengcheng Zhang, Fei Ye, Ting Zhao, Bingtao Liu, Qiang Li
BACKGROUND AND PURPOSE: Previously, we found genistein could sensitize cancer cells to low linear energy transfer (LET) X-rays via inhibiting DNA-PKcs activities. Especially, high-LET heavy ion produces more DNA double strand breaks (DSBs) than low-LET radiation. Thus, the study was designed to investigate the detailed molecular mechanisms of genistein on sensitizing cancer cells to heavy ions. MATERIALS AND METHODS: Human glioblastoma (GBM) cell lines with or without genistein pre-treatment were irradiated with high-LET carbon ions...
April 20, 2018: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/29642372/%C3%AF-3-and-%C3%AF-6-fatty-acids-modulate-conventional-and-atypical-protein-kinase-c-activities-in-a-brain-fatty-acid-binding-protein-dependent-manner-in-glioblastoma-multiforme
#8
Marwa E Elsherbiny, Hua Chen, Marwan Emara, Roseline Godbout
Glioblastoma multiforme (GBM) is a highly infiltrative brain cancer with a dismal prognosis. High levels of brain fatty acid binding protein (B-FABP) are associated with increased migration/infiltration in GBM cells, with a high ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) driving B-FABP-mediated migration. Since several protein kinase Cs (PKCs) are overexpressed in GBM and linked to migration, we explored a possible relationship between B-FABP and levels/activity of different PKCs, as a function of AA and DHA supplementation...
April 6, 2018: Nutrients
https://www.readbyqxmd.com/read/29594212/cell-line-dependent-effects-of-hypoxia-prior-to-irradiation-in-squamous-cell-carcinoma-lines
#9
Franziska Hauth, Mahmoud Toulany, Daniel Zips, Apostolos Menegakis
Purpose: To assess the impact of hypoxia exposure on cellular radiation sensitivity and survival of tumor cells with diverse intrinsic radiation sensitivity under normoxic conditions. Materials and methods: Three squamous cell carcinoma (SCC) cell lines, with pronounced differences in radiation sensitivity, were exposed to hypoxia prior, during or post irradiation. Cells were seeded in parallel for colony formation assay (CFA) and stained for γH2AX foci or processed for western blot analysis...
August 2017: Clinical and Translational Radiation Oncology
https://www.readbyqxmd.com/read/29587004/developing-a-phosphospecific-ihc-assay-as-a-predictive-biomarker-for-topoisomerase-i-inhibitors
#10
Koji Ando, Yara Hamade Tohme, Adithi Srinivasiah, Julian Taylor-Parker, Yevgeniya Harrington, Ankur K Shah, Eiji Oki, Mohan Brahmandam, Ajit K Bharti
Phosphorylation is the most extensively studied posttranslational modification of proteins. There are approximately 500 kinases known in the human genome. The kinase-activated pathways regulate almost every aspect of cell function and a deregulated kinase cascade leads to impaired cellular function. Impaired regulation of several kinase cascades, including the epidermal growth factor receptor (EGFR) pathway, leading to tumor pathogenesis, is well documented. Thus, a phosphospecific test with prognostic or predictive value was expected in oncology...
March 1, 2018: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
https://www.readbyqxmd.com/read/29574068/natural-product-toosendanin-reverses-the-resistance-of-human-breast-cancer-cells-to-adriamycin-as-a-novel-pi3k-inhibitor
#11
Wang Kai, Shan Yating, Ma Lin, Yang Kaiyong, Hua Baojin, Chen Yan, Yin Fangzhou, Yin Wu
Adriamycin (ADM) is a commonly used drug in clinical breast cancer treatment. However, some breast cancer types or breast cancers subjected to repeated ADM exposure develop strong resistance to ADM thus limiting its clinical efficacy. In this study, we found for the first time that toosendanin (TSN), a triterpenoid extracted from the traditional Chinese medicine Melia toosendan Sieb et Zucc, could successfully reverse adriamycin resistance in human breast cancer cells. Immunofluorescence and HPLC analysis demonstrated that TSN promoted adriamycin accumulation in breast cancer cells, especially in the nucleus...
March 21, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29549168/the-dna-pk-inhibitor-vx-984-enhances-the-radiosensitivity-of-glioblastoma-cells-grown-in-vitro-and-as-orthotopic-xenografts
#12
Cindy R Timme, Barbara H Rath, John W O'Neill, Kevin Camphausen, Philip J Tofilon
Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation...
March 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29545967/egfr-tyrosine-kinase-inhibitor-hs-10182-increases-radiation-sensitivity-in-non-small-cell-lung-cancers-with-egfr-t790m-mutation
#13
Yang Chen, Youyou Wang, Lujun Zhao, Ping Wang, Jifeng Sun, Rudi Bao, Chenghai Li, Ningbo Liu
Objective: To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC). Methods: Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups...
February 2018: Cancer Biology & Medicine
https://www.readbyqxmd.com/read/29545847/expression-of-dna-dependent-protein-kinase-catalytic-subunit-in-laryngeal-squamous-cell-carcinoma-and-its-importance
#14
Jian-Song Sun, Xiu-Hai Yang
The aim of the present study was to explore the expression and distribution of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in tumor tissues and adjacent normal mucosa tissues of patients with laryngeal squamous cell carcinoma (LSCC), and further analyze the association between the expression and the clinicopathological parameters of patients with LSCC. Clinical data of tumor tissues and corresponding adjacent normal mucosa tissues of pathologically diagnosed LSCC in 96 cases were collected in the present study...
April 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29527968/linp1-facilitates-dna-damage-repair-through-non-homologous-end-joining-nhej-pathway-and-subsequently-decreases-the-sensitivity-of-cervical-cancer-cells-to-ionizing-radiation
#15
Xuanxuan Wang, Hai Liu, Liming Shi, Xiaoli Yu, Yanjun Gu, Xiaonan Sun
LncRNA in non-homologous end joining (NHEJ) pathway 1 (LINP1) is an lncRNA which promotes therapeutic resistance in triple-negative breast cancer (TNBC). However, the expression and function of LINP1 in cervical cancer is not yet well-understood. In this study, we evaluated the expression levels of LINP1 in tumor tissues and cell lines of cervical cancer. We found that LINP1 associates with NHEJ proteins (Ku80 and DNA-PKcs). LINP1 translocates from cytosol to nucleus in response to irradiation. In addition, LINP1 knockdown significantly increases the levels of cleaved caspase3 and PARP, leading to enhanced cell apoptosis after ionizing radiation (IR)...
2018: Cell Cycle
https://www.readbyqxmd.com/read/29515758/expression-of-tdrd9-in-a-subset-of-lung-carcinomas-by-cpg-island-hypomethylation-protects-from-dna-damage
#16
Macarena Guijo, María Ceballos-Chávez, Elena Gómez-Marín, Laura Basurto-Cayuela, José C Reyes
Tudor domain containing protein 9 (TDRD9) is a RNA helicase normally expressed in the germline, where it is involved in the biosynthesis of PIWI-interacting RNAs (piRNAs). Here, we show that TDRD9 is highly expressed in a subset of non-small cell lung carcinomas and derived cell lines by hypomethylation of its CpG island. Furthermore, TDRD9 expression is associated with poor prognosis in lung adenocarcinoma. We find that downregulation of TDRD9 expression in TDRD9-positive cell lines causes a decrease in cell proliferation, S-phase cell cycle arrest, and apoptosis...
February 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29511621/robust-dna-repair-in-paxx-deficient-mammalian-cells
#17
Alisa Dewan, Mengtan Xing, Marie Benner Lundbæk, Raquel Gago-Fuentes, Carole Beck, Per Arne Aas, Nina-Beate Liabakk, Siri Sæterstad, Khac Thanh Phong Chau, Bodil Merete Kavli, Valentyn Oksenych
To ensure genome stability, mammalian cells employ several DNA repair pathways. Nonhomologous DNA end joining (NHEJ) is the DNA repair process that fixes double-strand breaks throughout the cell cycle. NHEJ is involved in the development of B and T lymphocytes through its function in V(D)J recombination and class switch recombination (CSR). NHEJ consists of several core and accessory factors, including Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, Artemis, and XLF. Paralog of XRCC4 and XLF (PAXX) is the recently described accessory NHEJ factor that structurally resembles XRCC4 and XLF and interacts with Ku70/Ku80...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29511619/normal-development-of-mice-lacking-paxx-the-paralogue-of-xrcc4-and-xlf
#18
Raquel Gago-Fuentes, Mengtan Xing, Siri Sæterstad, Antonio Sarno, Alisa Dewan, Carole Beck, Stefano Bradamante, Magnar Bjørås, Valentyn Oksenych
DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR). Inactivation of NHEJ factors Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, and Artemis impairs V(D)J recombination and blocks lymphocyte development. Paralogue of XRCC4 and XLF (PAXX) is an accessory NHEJ factor that has a significant impact on the repair of DNA lesions induced by ionizing radiation in human, murine, and chicken cells...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29482073/notch1-modulates-activity-of-dna-pkcs
#19
Marek Adamowicz, Fabrizio d'Adda di Fagagna, Jelena Vermezovic
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) controls one of the most frequently used DNA repair pathways in a cell, the non-homologous end joining (NHEJ) pathway. However, the exact role of DNA-PKcs in NHEJ remains poorly defined. Here we show that NOTCH1 attenuates DNA-PKcs-mediated autophosphorylation, as well as the phosphorylation of its specific substrate XRCC4. Surprisingly, NOTCH1-expressing cells do not display any significant impairment in the DNA damage repair, nor cellular survival, and remain sensitive to small molecule DNA-PKcs inhibitor...
March 2018: Mutation Research
https://www.readbyqxmd.com/read/29478807/the-histone-chaperones-asf1-and-caf-1-promote-mms22l-tonsl-mediated-rad51-loading-onto-ssdna-during-homologous-recombination-in-human-cells
#20
Ting-Hsiang Huang, Faith Fowler, Chin-Chuan Chen, Zih-Jie Shen, Barry Sleckman, Jessica K Tyler
The access-repair-restore model for the role of chromatin in DNA repair infers that chromatin is a mere obstacle to DNA repair. However, here we show that blocking chromatin assembly, via knockdown of the histone chaperones ASF1 or CAF-1 or a mutation that prevents ASF1A binding to histones, hinders Rad51 loading onto ssDNA during homologous recombination. This is a consequence of reduced recruitment of the Rad51 loader MMS22L-TONSL to ssDNA, resulting in persistent RPA foci, extensive DNA end resection, persistent activation of the ATR-Chk1 pathway, and cell cycle arrest...
March 1, 2018: Molecular Cell
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