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Vazhappilly Cijo George, H P Vasantha Rupasinghe
DNA damage caused by environmental agents often lead to many chronic diseases, including cancer. The present study aimed to understand the relative toxicity possessed by Bisphenol A (BPA) and Bisphenol S (BPS) on human bronchial epithelial cells (BEAS-2B). The cells were exposed to either BPA or BPS and evaluated for its cytotoxicity, reactive oxygen species (ROS), DNA fragmentation, phosphorylated histone protein (γ-H2AX) and DNA tail damage levels. Further, we also studied DNA damage response (DDR) and caspase-3 mechanisms, to evaluate its mechanism of cell death processes...
April 11, 2018: Environmental Toxicology and Pharmacology
Marek Adamowicz
ATM kinase is a master regulator of the DNA damage response (DDR). A recently published report from the d'Adda di Fagagna laboratory1 sheds a light onto our understanding of ATM activation. In this short-commentary we will expand on this and other work to perceive better some of the aspects of ATM regulation.
January 2018: Journal of immunological sciences
Geethani Bandara, Rosa Muñoz-Cano, Araceli Tobío, Yuzhi Yin, Hirsh D Komarow, Avanti Desai, Dean D Metcalfe, Ana Olivera
Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth...
2018: Frontiers in Immunology
Antoine Gaudreau-Lapierre, Daniel Garneau, Billel Djerir, Frédéric Coulombe, Théo Morin, Alexandre Marechal
The DNA Damage Response (DDR) uses a plethora of proteins to detect, signal, and repair DNA lesions. Delineating this response is critical to understand genome maintenance mechanisms. Since recruitment and exchange of proteins at lesions are highly dynamic, their study requires the ability to generate DNA damage in a rapid and spatially-delimited manner. Here, we describe procedures to locally induce DNA damage in human cells using a commonly available laser-scanning confocal microscope equipped with a 405 nm laser line...
March 20, 2018: Journal of Visualized Experiments: JoVE
Martin R Gill, Paul J Jarman, Swagata Halder, Michael G Walker, Hiwa K Saeed, Jim A Thomas, Carl Smythe, Kristijan Ramadan, Katherine A Vallis
Substitutionally inert ruthenium(ii) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen)2 (tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53-deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest...
January 28, 2018: Chemical Science
Theodoros Karantanos, Alison R Moliterno
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN...
March 30, 2018: Blood Reviews
Takeshi Terabayashi, Katsuhiro Hanada
Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in cells, tissues, organs, and organisms. Because genomes are constantly exposed to intrinsic and extrinsic genotoxic stress, cellular DNA repair machinery and proper DNA damage responses (DDR) have evolved to quickly eliminate genotoxic DNA lesions, thus maintaining the genome integrity suitably. In human, germline mutations in genes involved not only in cellular DNA repair pathways but also in cellular DDR machinery frequently predispose hereditary diseases associated with chromosome aberrations...
April 5, 2018: Cell Biology and Toxicology
Maria Prata-Sena, Bruno M Castro-Carvalho, Sandra Nunes, Bento Amaral, Paula Silva
Port wine is an internationally acclaimed fortified wine produced in Douro Demarcated Region (DDR) in Portugal, and recognized with protected designation of origin. This review represents a compilation of the known chromatic and aromatic descriptors of Port wine. A comprehensive review of literature is performed regarding the influence of geography, climate, soil, grapevine cultivars, and vitivinicultural practices on the unique Port wine attributes. This manuscript provides an extensive insight regarding the different aspects that influence the quality and uniqueness of Port wine, especially its main sensory attributes: colour, aroma, and flavour...
August 15, 2018: Food Chemistry
Zhenchuan Chen, Wei Zhang, Zhimin Yun, Xue Zhang, Feng Gong, Yunfang Wang, Shouping Ji, Ling Leng
In response to DNA damage, proliferating cell nuclear antigen (PCNA) has an important role as a positive regulator and as a scaffold protein associated with DNA damage bypass and repair pathways by serving as a platform for the recruitment of associated components. As demonstrated in the present study, the ubiquitin‑like modifier human leukocyte antigen F locus adjacent transcript 10 (FAT10), which binds to PCNA but has not previously been demonstrated to be associated with the DNA damage response (DDR), is induced by ultraviolet/ionizing radiation and VP‑16 treatment in HeLa cells...
April 5, 2018: Molecular Medicine Reports
Xu Feng, Mengmeng Sun, Wenyuan Han, Yun Xiang Liang, Qunxin She
Previously it was shown that UV irradiation induces a strong upregulation of tfb3 coding for a paralog of the archaeal transcriptional factor B (TFB) in Sulfolobus solfataricus, a crenarchaea. To investigate the function of this gene in DNA damage response (DDR), tfb3 was inactivated by gene deletion in Sulfolobus islandicus and the resulting Δtfb3 was more sensitive to DNA damage agents than the original strain. Transcriptome analysis revealed that a large set of genes show TFB3-dependent activation, including genes of the ups operon and ced system...
March 30, 2018: Nucleic Acids Research
Theo A Knijnenburg, Linghua Wang, Michael T Zimmermann, Nyasha Chambwe, Galen F Gao, Andrew D Cherniack, Huihui Fan, Hui Shen, Gregory P Way, Casey S Greene, Yuexin Liu, Rehan Akbani, Bin Feng, Lawrence A Donehower, Chase Miller, Yang Shen, Mostafa Karimi, Haoran Chen, Pora Kim, Peilin Jia, Eve Shinbrot, Shaojun Zhang, Jianfang Liu, Hai Hu, Matthew H Bailey, Christina Yau, Denise Wolf, Zhongming Zhao, John N Weinstein, Lei Li, Li Ding, Gordon B Mills, Peter W Laird, David A Wheeler, Ilya Shmulevich, Raymond J Monnat, Yonghong Xiao, Chen Wang
DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer...
April 3, 2018: Cell Reports
Venturina Stagni, Claudia Cirotti, Daniela Barilà
Ataxia-telangiectasia mutated kinase (ATM) plays a central role in the DNA damage response (DDR) and mutations in its gene lead to the development of a rare autosomic genetic disorder, ataxia telangiectasia (A-T) characterized by neurodegeneration, premature aging, defects in the immune response, and higher incidence of lymphoma development. The ability of ATM to control genome stability several pointed to ATM as tumor suppressor gene. Growing evidence clearly support a significant role of ATM, in addition to its master ability to control the DDR, as principle modulator of oxidative stress response and mitochondrial homeostasis, as well as in the regulation of autophagy, hypoxia, and cancer stem cell survival...
2018: Frontiers in Oncology
Nicholas Pulliam, Fang Fang, Ali R Ozes, Jessica Tang, Adeoluwa Adewuyi, Harold N Keer, John F Lyons, Stephen B Baylin, Daniela Matei, Harikrishna Nakshatri, Feyruz V Rassool, Kathy D Miller, Kenneth P Nephew
PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair (DDR) and our previous studies demonstrating DNMTis ability to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status...
April 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Eloy Andrés Pérez-Yépez, Héctor Iván Saldívar-Cerón, Olga Villamar-Cruz, Carlos Pérez-Plasencia, Luis Enrique Arias-Romero
p21-activated kinase 1 (PAK1) is a serine/threonine kinase activated by the small GTPases Rac1 and Cdc42. It is located in the chromosome 11q13 and is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors. This enzyme plays a pivotal role in the control of a number of fundamental cellular processes by phosphorylating its downstream substrates. In addition to its role in the cytoplasm, it is well documented that PAK1 also plays crucial roles in the nucleus participating in mitotic events and gene expression through its association and/or phosphorylation of several transcription factors, transcriptional co-regulators and cell cycle-related proteins, including Aurora kinase A (AURKA), polo-like kinase 1 (PLK1), the forkhead transcription factor (FKHR), estrogen receptor α (ERα), and Snail...
March 21, 2018: DNA Repair
Diana Romero
No abstract text is available yet for this article.
March 28, 2018: Nature Reviews. Clinical Oncology
Nafiseh Chalabi Hagkarim, Ellis L Ryan, Philip J Byrd, Robert Hollingworth, Neil J Shimwell, Angelo Agathanggelou, Manon Vavasseur, Viktoria Kolbe, Thomas Speiseder, Thomas Dobner, Grant S Stewart, Roger J Grand
Infection by most DNA viruses activates a cellular DNA damage response (DDR), which may be to the detriment or advantage of the virus. In the case of adenoviruses, they neutralise anti-viral effects of DDR activation by targeting a number of proteins for rapid proteasome-mediated degradation. We have now identified a novel DDR protein, tankyrase 1 binding protein 1 (TNKS1BP1 also known as Tab182), which is degraded during infection by adenovirus 5 and adenovirus 12. In both cases, degradation requires the action of E1B55K and E4orf6 viral proteins and is mediated through the proteasome by the action of cullin-based cellular E3 ligases...
March 28, 2018: Journal of Virology
Rajib Ghosh, Sanchita Roy, Sonia Franco
DNA Damage Response (DDR) and DNA repair pathways are emerging as potent, ubiquitous suppressors of innate immune signaling in human cells. Here, we show that human cells surviving depletion of the Single Strand Break (SSB) repair protein PARP1 undergo p21-dependent senescence or cell cycle checkpoint activation in the context of activation of innate immune signaling, or viral mimicry. Specifically, we observe induction of a large number of interferon-stimulated genes (ISGs) and multiple pattern recognition receptors (PRRs; including RIG-I, MDA-5, MAVS, TLR3 and STING) and increased nuclear IRF3 staining...
2018: PloS One
Lin Yang, Guanghai Yang, Yingjun Ding, Yuhong Dai, Sanpeng Xu, Qiuyun Guo, Aini Xie, Guangyuan Hu
Pancreatic cancer is among the most aggressive human cancers, and is resistant to regular chemotherapy and radiotherapy. The AT-rich interactive domain containing protein 1A ( ARID1A ) gene, a crucial chromatin remodeling gene, mutates frequently in a broad spectrum of cancers, including pancreatic cancer. Recent evidence suggests that ARID1A acts as tumor suppressor and plays an important role in DNA damage repair (DDR). However, the effect of ARID1A on the radiosensitivity of pancreatic cancer remains unclear...
2018: Journal of Cancer
W Le, L Qi, C Xu, Z Xiang, Z Mao, J Zhang, J Xu, D Wu
The present study was designed to detect DNA repair response through the homologous recombination pathway in mouse spermatogonial stem cells. Mouse spermatogonial stem cells (mSSCs) were obtained from the adult DBA/2 mouse testes by MACS sorting. mSSCs and mice animals were divided into four groups (30 min, 2, 24 h, control) and treated with ionizing irradiation while the control group received pseudo-irradiation. Proteins involved in the homologous recombination pathway (γH2AX, ATM, RAD51, CtIP, and RPA2) were assessed in mSSCs both in vitro and in vivo...
March 25, 2018: Andrology
Shinji Miwa, Robert M Hoffman
DNA damage repair in response to UVC irradiation was imaged in cancer cells growing in Gelfoam® histoculture. UVC-induced DNA damage repair was imaged with green fluorescent protein (GFP) fused to the DNA damage response (DDR)-related binding protein 53BP1 in MiaPaCa-2 human pancreatic cancer cells. Three-dimensional Gelfoam® histocultures and confocal imaging enabled 53BP1-GFP nuclear foci to be observed within 1 h after UVC irradiation, indicating the onset of DNA damage repair response. Induction of UV-induced 53BP1-GFP focus formation was limited up to a depth of 40 μm in Gelfoam®  histoculture of MiaPaCa-2 cells, indicating this was the depth limit of UVC irradiation...
2018: Methods in Molecular Biology
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