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https://www.readbyqxmd.com/read/28646552/targeting-histone-deacetylase-4-ubc9-impairs-dna-repair-for-radiosensitization-of-hepatocellular-carcinoma-cells
#1
Chiao-Ling Tsai, Wei-Lin Liu, Feng-Ming Hsu, Po-Sheng Yang, Ruoh-Fang Yen, Kai-Yuan Tzen, Ann-Lii Cheng, Pei-Jer Chen, Jason Chia-, Hsien Cheng
Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach was to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or shRNA to knock down expression of HDAC4, and then irradiated (2...
June 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28646206/crispr-cas9-mediated-genome-editing-via-postnatal-administration-of-aav-vector-cures-haemophilia-b-mice
#2
Tsukasa Ohmori, Yasumitsu Nagao, Hiroaki Mizukami, Asuka Sakata, Shin-Ichi Muramatsu, Keiya Ozawa, Shin-Ichi Tominaga, Yutaka Hanazono, Satoshi Nishimura, Osamu Nureki, Yoichi Sakata
Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28645381/examining-dna-double-strand-break-repair-in-a-cell-cycle-dependent-manner
#3
Janapriya Saha, Shih-Ya Wang, Anthony J Davis
DNA double-strand breaks (DSBs) are deleterious DNA lesions that must be properly repaired to maintain genome stability. Agents, generated both exogenously (environmental radiation, dental X-rays, etc.) and endogenously (reactive oxygen species, DNA replication, V(D)J recombination, etc.), induce numerous DSBs every day. To counter these DSBs, there are two major repair pathways in mammalian cells, nonhomologous end joining (NHEJ) and homologous recombination (HR). NHEJ directly mediates the religation of the broken DNA molecule and is active in all phases of the cell cycle...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28645371/ensemble-and-single-molecule-analysis-of-non-homologous-end-joining-in-frog-egg-extracts
#4
Thomas G W Graham, Johannes C Walter, Joseph J Loparo
Non-homologous end joining (NHEJ) repairs the majority of DNA double-strand breaks in human cells, yet the detailed order of events in this process has remained obscure. Here, we describe how to employ Xenopus laevis egg extract for the study of NHEJ. The egg extract is easy to prepare in large quantities, and it performs efficient end joining that requires the core end joining proteins Ku, DNA-PKcs, XLF, XRCC4, and DNA ligase IV. These factors, along with the rest of the soluble proteome, are present at endogenous concentrations, allowing mechanistic analysis in a system that begins to approximate the complexity of cellular end joining...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28643258/crispr-cas9-mediated-targeted-knockin-of-exogenous-reporter-genes-in-zebrafish
#5
Atsuo Kawahara
Genome editing technologies such as ZFN, TALEN, and CRISPR/Cas9 efficiently induce DNA double-stranded breaks (DSBs) at a targeted genomic locus, often resulting in a frameshift-mediated target gene disruption. It remains difficult to perform targeted integration of exogenous genes by genome editing technologies. DSBs can be restored through DNA repair mechanisms, such as non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination (HR). It is well known that HR facilitates homology-dependent integration of donor DNA template into a targeted locus...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28643248/computational-prediction-of-crispr-cas9-target-sites-reveals-potential-off-target-risks-in-human-and-mouse
#6
Qingbo Wang, Kumiko Ui-Tei
The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system is a prominent genome engineering technology. In the CRISPR/Cas system, the RNA-guided endonuclease Cas protein introduces a DNA double-stranded break at the genome position recognized by a guide RNA (gRNA) based on complementary base-pairing of about 20-nucleotides in length. The 8- or 12-mer gRNA sequence in the proximal region is especially important for target recognition, and the genes with sequence complementarity to such regions are often disrupted...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28642840/cytolethal-distending-toxin-enhances-radiosensitivity-in-prostate-cancer-cells-by-regulating-autophagy
#7
Hwai-Jeng Lin, Hsin-Ho Liu, Chia-Der Lin, Min-Chuan Kao, Yu-An Chen, Chuan Chiang-Ni, Zhi-Pei Jiang, Mei-Zi Huang, Chun-Jung Lin, U-Ging Lo, Li-Chiung Lin, Cheng-Kuo Lai, Ho Lin, Jer-Tsong Hsieh, Cheng-Hsun Chiu, Chih-Ho Lai
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni contains three subunits: CdtA, CdtB, and CdtC. Among these three toxin subunits, CdtB is the toxic moiety of CDT with DNase I activity, resulting in DNA double-strand breaks (DSB) and, consequently, cell cycle arrest at the G2/M stage and apoptosis. Radiation therapy is an effective modality for the treatment of localized prostate cancer (PCa). However, patients often develop radioresistance. Owing to its particular biochemical properties, we previously employed CdtB as a therapeutic agent for sensitizing radioresistant PCa cells to ionizing radiation (IR)...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28642363/nuclear-phosphorylated-dicer-processes-double-stranded-rna-in-response-to-dna-damage
#8
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...
June 22, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28641523/radiosensitizing-effect-of-electrochemotherapy-a-systematic-review-of-protocols-and-efficiency
#9
Zohre Rezaee, Ali Yadollahpour, Samaneh Rashidi, Pramod S Kunwar
OBJECTIVE: Electrochemotherapy (ECT) is a combination of electroporation (EP) and chemotherapy and has been reported as a potential radiosensitizing agent for radiation therapy. The main objective of this study was to systematically review of the literature to evaluate the effectiveness of ECT in sensitization of tumors to ionization radiation. In addition, the clinical considerations and mechanisms of action of radiosensitizing effect are discussed. METHODS: The databases of Medline (PubMed), Embase, Scopus, Cochrane library, Web of Science, Biomed central, Science Direct, and Google scholar up to March 30th 2017 were explored...
June 21, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28641126/dna-requirements-for-interaction-of-the-c-terminal-region-of-ku80-with-the-dna-dependent-protein-kinase-catalytic-subunit-dna-pkcs
#10
Sarvan Kumar Radhakrishnan, Susan P Lees-Miller
Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks (DSBs) in human cells. Critical to NHEJ is the DNA-dependent interaction of the Ku70/80 heterodimer with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme. However, precisely how Ku recruits DNA-PKcs to DSBs ends to enhance its kinase activity has remained enigmatic, with contradictory findings reported in the literature. Here we address the role of the Ku80 C-terminal region (CTR) in the DNA-dependent interaction of Ku70/80 with DNA-PKcs using purified components and defined DNA structures...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28640454/direct-quantification-of-gamma-h2ax-by-cell-based-high-throughput-screening-for-evaluation-of-genotoxicity-of-pesticides-in-a-human-thyroid-cell-lines
#11
Jerome M Hershman, Bryan France, Kevin Hon, Robert Damoiseaux
Genotoxicity is thought to be the cause of many cancers. Genotoxicity due to environmental toxins may be partly responsible for the dramatic increase in the incidence of papillary thyroid cancer over the past two decades. Here, we present a fully automatable assay platform that directly quantifies the phosphorylation of nuclear histone gamma H2AX (γH2AX), a specific cellular marker for DNA double strand breaks (DSBs) via immunohistochemistry and laser scanning cytometry. It multiplexes γH2AX with total cell number measured as propidium iodide and calculates the percentage of cells with DSBs...
June 22, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28639949/comet-assay-in-evaluating-deoxyribonucleic-acid-damage-after-out-of-hospital-cardiac-arrest
#12
Radka Hazuková, Martina Rezácová, Renata Köhlerová, Tomáš Tomek, Eva Cermáková, Jaromír Kocí, Miloslav Pleskot
OBJECTIVE: This study aimed to investigate whether out-of-hospital cardiac arrest (OHCA) may induce severe DNA damage measured using comet assay in successfully resuscitated humans and to evaluate a short-term prognostic role. METHODS: In this prospective, controlled, blinded study (1/2013-1/2014), 41 patients (age, 63±14 years) successfully resuscitated from non traumatic OHCA and 10 healthy controls (age, 53±17 years) were enrolled. DNA damage [double-strand breaks (DSBs) and single-strand breaks (SSBs)] was measured using comet assay in peripheral lymphocytes sampled at admission...
June 22, 2017: Anatolian Journal of Cardiology
https://www.readbyqxmd.com/read/28638454/downregulation-of-mitochondrial-single-stranded-dna-binding-protein-ssbp1-induces-mitochondrial-dysfunction-and-increases-the-radiosensitivity-in-non-small-cell-lung-cancer-cells
#13
You Wang, Liu Hu, Ximei Zhang, Hong Zhao, Hui Xu, Yuehua Wei, Huangang Jiang, Conghua Xie, Yunfeng Zhou, Fuxiang Zhou
Radiotherapy is one of the major therapeutic strategies for human non-small cell lung cancer (NSCLC), but intrinsic radioresistance of cancer cells makes a further improvement of radiotherapy for NSCLC challenging. Mitochondrial function is frequently dysregulated in cancer cells for adaptation to the changes of tumor microenvironment after exposure to radiation. Therefore, targeting mitochondrial biogenesis and bioenergetics is an attractive strategy to sensitize cancer cells to radiation therapy. In this study, we found that downregulation of single-strand DNA-binding protein 1 (SSBP1) in H1299 cells was associated with inducing mitochondrial dysfunction and increasing radiosensitivity to ionizing radiation...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28637749/cell-cycle-dependent-spatial-segregation-of-telomerase-from-sites-of-dna-damage
#14
Faissal Ouenzar, Maxime Lalonde, Hadrien Laprade, Geneviève Morin, Franck Gallardo, Samuel Tremblay-Belzile, Pascal Chartrand
Telomerase can generate a novel telomere at DNA double-strand breaks (DSBs), an event called de novo telomere addition. How this activity is suppressed remains unclear. Combining single-molecule imaging and deep sequencing, we show that the budding yeast telomerase RNA (TLC1 RNA) is spatially segregated to the nucleolus and excluded from sites of DNA repair in a cell cycle-dependent manner. Although TLC1 RNA accumulates in the nucleoplasm in G1/S, Pif1 activity promotes TLC1 RNA localization in the nucleolus in G2/M...
June 21, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28637007/c-fos-dependent-mir-22-targets-mdc1-and-regulates-dna-repair-in-terminally-differentiated-cells
#15
Jung-Hee Lee, Seon-Joo Park, Seok Won Kim, Gurusamy Hariharasudhan, Sung-Mi Jung, Semo Jun, Jeongsik Yong, Ho Jin You
Terminally differentiated cells have a reduced capacity to repair double-stranded breaks (DSB) in DNA, however, the underlying molecular mechanism remains unclear. Here, we show that miR-22 is upregulated during postmitotic differentiation of human breast MCF-7 cells, hematopoietic HL60 and K562 cells. Increased expression of miR-22 in differentiated cells was associated with decreased expression of MDC1, a protein that plays a key role in the response to DSBs. This downregulation of MDC1 was accompanied by reduced DSB repair, impaired recruitment of the protein to the site of DNA damage following IR...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28635637/a-short-term-biological-indicator-for-long-term-kidney-damage-after-radionuclide-therapy-in-mice
#16
Giovanni Pellegrini, Klaudia Siwowska, Stephanie Haller, Daniel J Antoine, Roger Schibli, Anja Kipar, Cristina Müller
Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that-in this case-cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application...
June 21, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28634400/chronic-treatment-with-cisplatin-induces-chemoresistance-through-the-tip60-mediated-fanconi-anemia-and-homologous-recombination-repair-pathways
#17
Wen-Pin Su, Yen-Chih Ho, Cheng-Kuei Wu, Sen-Huei Hsu, Jia-Lin Shiu, Jheng-Cheng Huang, Song-Bin Chang, Wen-Tai Chiu, Jan-Jong Hung, Tsung-Lin Liu, Wei-Sheng Wu, Pei-Yu Wu, Wu-Chou Su, Jang-Yang Chang, Hungjiun Liaw
The Fanconi anemia pathway in coordination with homologous recombination is essential to repair interstrand crosslinks (ICLs) caused by cisplatin. TIP60 belongs to the MYST family of acetyltransferases and is involved in DNA repair and regulation of gene transcription. Although the physical interaction between the TIP60 and FANCD2 proteins has been identified that is critical for ICL repair, it is still elusive whether TIP60 regulates the expression of FA and HR genes. In this study, we found that the chemoresistant nasopharyngeal carcinoma cells, derived from chronic treatment of cisplatin, show elevated expression of TIP60...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634224/igh-myc-translocation-associates-with-brca2-deficiency-and-synthetic-lethality-to-parp1-inhibitors
#18
Silvia Maifrede, Kayla Martin, Paulina Podszywalow-Bartnicka, Katherine Sullivan, Samantha K Langer, Reza Nejadi, Yashodhara Dasgupta, Michael Hulse, Daniel Gritsyuk, Margaret Nieborowska-Skorska, Lena N Lupey-Green, Huaqing Zhao, Katarzyna Piwocka, Mariusz A Wasik, Italo Tempera, Tomasz Skorski
Burkitt lymphoma/leukemia (BL) cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate a high number of potentially lethal DNA double-strand breaks (DSBs) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28634159/a-role-for-the-nonsense-mediated-mrna-decay-pathway-in-maintaining-genome-stability-in-caenorhabditis-elegans
#19
Víctor González-Huici, Bin Wang, Anton Gartner
Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand-breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hypersensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) kinase involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signalling pathways...
June 20, 2017: Genetics
https://www.readbyqxmd.com/read/28633670/preclinical-anti-myeloma-activity-of-edo-s101-a-new-bendamustine-derived-molecule-with-added-hdaci-activity-through-potent-dna-damage-induction-and-impairment-of-dna-repair
#20
Ana-Alicia López-Iglesias, Ana B Herrero, Marta Chesi, Laura San-Segundo, Lorena González-Méndez, Susana Hernández-García, Irena Misiewicz-Krzeminska, Dalia Quwaider, Montserrat Martín-Sánchez, Daniel Primo, Teresa Paíno, P Leif Bergsagel, Thomas Mehrling, Marcos González-Díaz, Jesús F San-Miguel, María-Victoria Mateos, Norma C Gutiérrez, Mercedes Garayoa, Enrique M Ocio
BACKGROUND: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. METHODS: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents...
June 20, 2017: Journal of Hematology & Oncology
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