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https://www.readbyqxmd.com/read/28806777/a-synthetic-sickness-screen-for-senescence-re-engagement-targets-in-mutant-cancer-backgrounds
#1
Claire J Cairney, Lauren S Godwin, Alan E Bilsland, Sharon Burns, Katrina H Stevenson, Lynn McGarry, John Revie, Jon D Moore, Ceri M Wiggins, Rebecca S Collinson, Clare Mudd, Elpida Tsonou, Mahito Sadaie, Dorothy C Bennett, Masashi Narita, Christopher J Torrance, W Nicol Keith
Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28796249/rho-inhibition-by-lovastatin-affects-apoptosis-and-dsb-repair-of-primary-human-lung-cells-in-vitro-and-lung-tissue-in-vivo-following-fractionated-irradiation
#2
Verena Ziegler, Christian Henninger, Ioannis Simiantonakis, Marcel Buchholzer, Mohammad Reza Ahmadian, Wilfried Budach, Gerhard Fritz
Thoracic radiotherapy causes damage of normal lung tissue, which limits the cumulative radiation dose and, hence, confines the anticancer efficacy of radiotherapy and impacts the quality of life of tumor patients. Ras-homologous (Rho) small GTPases regulate multiple stress responses and cell death. Therefore, we investigated whether pharmacological targeting of Rho signaling by the HMG-CoA-reductase inhibitor lovastatin influences ionizing radiation (IR)-induced toxicity in primary human lung fibroblasts, lung epithelial and lung microvascular endothelial cells in vitro and subchronic mouse lung tissue damage following hypo-fractionated irradiation (4x4 Gy)...
August 10, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28781144/regulation-of-repair-pathway-choice-at-two-ended-dna-double-strand-breaks
#3
REVIEW
Atsushi Shibata
A DNA double-strand break (DSB) is considered to be a critical DNA lesion because its misrepair can cause severe mutations, such as deletions or chromosomal translocations. For the precise repair of DSBs, the repair pathway that is optimal for the particular circumstance needs to be selected. Non-homologous end joining (NHEJ) functions in G1/S/G2 phase, while homologous recombination (HR) becomes active only in S/G2 phase after DNA replication. DSB end structure is another factor affecting the repair pathway...
July 29, 2017: Mutation Research
https://www.readbyqxmd.com/read/28753066/a-single-exposure-to-low-or-high-let-radiation-induces-persistent-genomic-damage-in-mouse-epithelial-cells-in-vitro-and-in-lung-tissue
#4
Erica Werner, Ya Wang, Paul W Doetsch
Exposures to low- and high-linear energy transfer (LET) radiation induce clustered damage in DNA that is difficult to repair. These lesions are manifested as DNA-associated foci positive for DNA repair proteins and have been shown to persist in vitro and in vivo for days in several cell types and tissues in response to low-LET radiation. Although in some experimental conditions these residual foci have been linked with genomic instability and chromosomal aberrations, it remains poorly understood what type of damage they represent...
July 28, 2017: Radiation Research
https://www.readbyqxmd.com/read/28751496/nup153-and-nup50-promote-recruitment-of-53bp1-to-dna-repair-foci-by-antagonizing-brca1-dependent-events
#5
Douglas R Mackay, Amanda C Howa, Theresa L Werner, Katharine S Ullman
DNA double strand breaks are typically repaired through either the high-fidelity process of homologous recombination (HR), in which BRCA1 plays a key role, or the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in binding to damage sites, where it protects the DNA ends from resection. The nucleoporin Nup153 has been implicated in the DNA damage response, attributed to a role in promoting nuclear import of 53BP1...
July 27, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28747595/nac-ameliorates-dental-composite-induced-dna-double-strand-breaks-and-chromatin-condensation
#6
Panorea Styllou, Marianthi Styllou, Reinhard Hickel, Christof Högg, Franz Xaver Reichl, Harry Scherthan
Released (co)monomers from dental composite components can induce DNA damage of which DNA double-strand breaks (DSBs) threaten genome integrity. Here, we tested whether the administration of the antioxidant N-acetylcysteine (NAC) is able to reduce the dental composite-induced DSBs in primary human gingiva fibroblasts. The dental composites Bis-GMA (bisphenol-A-glycerolate dimethacrylate), GMA (glycidyl methacrylate), HEMA (2-hydroxyethyl methacrylate) and TEGDMA (triethyleneglycol dimethacrylate) were found to induce co-localizing microscopic nuclear foci numbers of the DSB markers γ-H2AX and 53BP1 per cell in the order: GMA>Bis-GMA>TEGDMA>HEMA...
July 26, 2017: Dental Materials Journal
https://www.readbyqxmd.com/read/28747557/%C3%AE-h2ax-53bp1-and-rad51-protein-foci-changes-in-mesenchymal-stem-cells-during-prolonged-x-ray-irradiation
#7
Anastasia Tsvetkova, Ivan V Ozerov, Margarita Pustovalova, Anna Grekhova, Petr Eremin, Natalia Vorobyeva, Ilya Eremin, Andrey Pulin, Vadim Zorin, Pavel Kopnin, Sergey Leonov, Alex Zhavoronkov, Dmitry Klokov, Andreyan N Osipov
At high exposure levels ionizing radiation is a carcinogen. Little is known about how human stem cells, which are known to contribute to tumorigenesis, respond to prolonged radiation exposures. We studied formation of DNA double strand breaks, accessed as γH2AX and 53BP1 foci, in human mesenchymal stem cells (MSCs) exposed to either acute (5400 mGy/h) or prolonged (270 mGy/h) X-irradiation. We show a linear γH2AX and 53BP1 dose response for acute exposures. In contrast, prolonged exposure resulted in a dose-response curve that had an initial linear portion followed by a plateau...
July 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28746371/ionizing-radiation-response-of-primary-normal-human-lens-epithelial-cells
#8
Nobuyuki Hamada
Whilst the cataractogenic potential of ionizing radiation has been known for over the past 120 years, little is known about radiation responses of lens cells. Our previous work was the first to evaluate the radiosensitivity of lens cells with the clonogenic assay, documenting that the survival of HLEC1 human lens epithelial cells is comparable to that of WI-38 human lung fibroblasts. Moreover, HLEC1 cells were found to contain subsets where irradiation stimulates proliferation or facilitates formation of abortive colonies with fewer cells than human fibroblasts...
2017: PloS One
https://www.readbyqxmd.com/read/28731465/pr-set7-deficiency-limits-uterine-epithelial-population-growth-hampering-postnatal-gland-formation-in-mice
#9
Tongtong Cui, Bo He, Shuangbo Kong, Chan Zhou, Hangxiao Zhang, Zhangli Ni, Haili Bao, Jingtao Qiu, Qiliang Xin, Danny Reinberg, John P Lydon, Jinhua Lu, Haibin Wang
Formation of secretary endometrial glands in the uterus known as adenogenesis is a typical process of branching morphogenesis involving dynamic epithelial growth and differentiation. Unsuccessful adenogenesis often leads to female infertility. However, it remains largely unexplored so far regarding the epigenetic machinery governing normal endometrial gland formation. Here, we demonstrated that PR-Set7, an epigenetic regulator for H4K20me1 modification, was extensively expressed in the postnatal uteri, and its conditional deletion resulted in a complete lack of endometrial glands and infertility in mice...
July 21, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28716689/brg1-and-smarcal1-transcriptionally-co-regulate-drosha-dgcr8-and-dicer-in-response-to-doxorubicin-induced-dna-damage
#10
Ketki Patne, Radhakrishnan Rakesh, Vijendra Arya, Upasana Bedi Chanana, Ramesh Sethy, Pynskhem Bok Swer, Rohini Muthuswami
Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known. In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin...
July 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28700933/inhibition-of-rif1-by-scai-allows-brca1-mediated-repair
#11
Shin-Ya Isobe, Koji Nagao, Naohito Nozaki, Hiroshi Kimura, Chikashi Obuse
DNA double-strand breaks (DSBs) are repaired by either the homology-directed repair (HDR) or the non-homologous end-joining (NHEJ) pathway. RIF1 (RAP1-interacting factor homolog) was recently shown to stimulate NHEJ through an interaction with 53BP1 (p53-binding protein 1) phosphorylated at S/TQ sites, but the molecular mechanism underlying pathway choice remains unclear. Here, we show that SCAI (suppressor of cancer cell invasion) binds to 53BP1 phosphorylated at S/TP sites and facilitates HDR. Upon DNA damage, RIF1 immediately accumulates at damage sites and then gradually dissociates from 53BP1 and is subsequently replaced with SCAI...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28700353/chiral-platinum-ii-4-2-3-dihydroxypropyl-formamide-oxo-aporphine-foa-complexes-promote-tumor-cells-apoptosis-by-directly-targeting-g-quadruplex-dna-in-vitro-and-in-vivo
#12
Qi-Pin Qin, Jiao-Lan Qin, Ming Chen, Yu-Lan Li, Ting Meng, Jie Zhou, Hong Liang, Zhen-Feng Chen
Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(-)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28689661/nuclear-acetyl-coa-production-by-acly-promotes-homologous-recombination
#13
Sharanya Sivanand, Seth Rhoades, Qinqin Jiang, Joyce V Lee, Joseph Benci, Jingwen Zhang, Salina Yuan, Isabella Viney, Steven Zhao, Alessandro Carrer, Michael J Bennett, Andy J Minn, Aalim M Weljie, Roger A Greenberg, Kathryn E Wellen
While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28659469/atm-loss-leads-to-synthetic-lethality-in-brca1-brct-mutant-mice-associated-with-exacerbated-defects-in-homology-directed-repair
#14
Chun-Chin Chen, Elizabeth M Kass, Wei-Feng Yen, Thomas Ludwig, Mary Ellen Moynahan, Jayanta Chaudhuri, Maria Jasin
BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the Brca1(S1598F) mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in Brca1(S1598F) cells...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28652056/oxidative-stress-contributes-to-hepatocyte-growth-factor-dependent-pro-senescence-activity-of-ovarian-cancer-cells
#15
Justyna Mikuła-Pietrasik, Paweł Uruski, Martyna Pakuła, Konstantin Maksin, Sebastian Szubert, Aldona Woźniak, Eryk Naumowicz, Dariusz Szpurek, Andrzej Tykarski, Krzysztof Książek
The cancer-promoting activity of senescent peritoneal mesothelial cells (HPMCs) has already been well evidenced both in vitro and in vivo. Here we sought to determine if ovarian cancer cells may activate senescence in HPMCs. The study showed that conditioned medium (CM) from ovarian cancer cells (OVCAR-3, SKOV-3, A2780) inhibited growth and promoted the development of senescence phenotype (increased SA-β-Gal, γ-H2A.X, 53BP1, and decreased Cx43) in HPMCs. An analysis of tumors isolated from the peritoneum of patients with ovarian cancer revealed an abundance of senescent HPMCs in proximity to cancerous tissue...
June 24, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28642363/nuclear-phosphorylated-dicer-processes-double-stranded-rna-in-response-to-dna-damage
#16
Kaspar Burger, Margarita Schlackow, Martin Potts, Svenja Hester, Shabaz Mohammed, Monika Gullerova
The endoribonuclease Dicer is a key component of the human RNA interference pathway and is known for its role in cytoplasmic microRNA production. Recent findings suggest that noncanonical Dicer generates small noncoding RNA to mediate the DNA damage response (DDR). Here, we show that human Dicer is phosphorylated in the platform-Piwi/Argonaute/Zwille-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks...
August 7, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28636420/tirr-and-53bp1-partners-in-arms
#17
Pascal Drané, Dipanjan Chowdhury
No abstract text is available yet for this article.
July 3, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28631426/hsp90%C3%AE-regulates-atm-and-nbn-functions-in-sensing-and-repair-of-dna-double-strand-breaks
#18
EDITORIAL
Rosa Pennisi, Antonio Antoccia, Stefano Leone, Paolo Ascenzi, Alessandra di Masi
The molecular chaperone heat shock protein 90 (Hsp90α) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ataxia-telangiectasia-mutated kinase (ATM) and nibrin (NBN), but not 53BP1, RAD50, and MRE11, are Hsp90α clients as the Hsp90α inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cell lines...
August 2017: FEBS Journal
https://www.readbyqxmd.com/read/28614780/53bp1-keep-an-eye-on-merotely
#19
Mengfan Tang, Junjie Chen
No abstract text is available yet for this article.
July 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611389/nuclear-tradd-prevents-dna-damage-mediated-death-by-facilitating-non-homologous-end-joining-repair
#20
Gi-Bang Koo, Jae-Hoon Ji, Hyeseong Cho, Michael J Morgan, You-Sun Kim
TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, the underlying function of nuclear TRADD is poorly understood. Here we demonstrate that cytoplasmic TRADD translocates to DNA double-strand break sites (DSBs) during the DNA damage response (DDR). Deficiency of TRADD or its sequestration in cytosol leads to accumulation of γH2AX-positive foci in response to DNA damage, which is reversed by nuclear TRADD expression...
June 13, 2017: Scientific Reports
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