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https://www.readbyqxmd.com/read/28931330/sequential-molecular-changes-and-dynamic-oxidative-stress-in-high-grade-serous-ovarian-carcinogenesis
#1
Hiroshi Kobayashi, Kenji Ogawa, Naoki Kawahara, Kana Iwai, Emiko Niiro, Sachiko Morioka, Yuki Yamada
The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English-language literature between 2005 and 2017. Clinicopathological features analysis provide a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC...
September 21, 2017: Free Radical Research
https://www.readbyqxmd.com/read/28921956/recognition-of-dna-supercoil-geometry-by-mycobacterium-tuberculosis-gyrase
#2
Rachel E Ashley, Tim R Blower, James M Berger, Neil Osheroff
Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M...
September 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28915668/nsc30049-inhibits-chk1-pathway-in-5-fu-resistant-crc-bulk-and-stem-cell-populations
#3
Satya Narayan, Aruna S Jaiswal, Ritika Sharma, Akbar Nawab, Lizette Vila Duckworth, Brian K Law, Maria Zajac-Kaye, Thomas J George, Jay Sharma, Arun K Sharma, Robert A Hromas
The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914393/costunolide-induces-micronuclei-formation-chromosomal-aberrations-cytostasis-and-mitochondrial-mediated-apoptosis-in-chinese-hamster-ovary-cells
#4
Soma Shiva Nageswara Rao Singireesu, Sunil Misra, Sujan Kumar Mondal, Suresh Yerramsetty, Nivedita Sahu, Suresh Babu K
Costunolide (CE) is a sesquiterpene lactone well-known for its antihepatotoxic, antiulcer, and anticancer activities. The present study focused on the evaluation of the cytogenetic toxicity and cellular death-inducing potential of CE in CHO cells, an epithelial cell line derived from normal ovary cells of Chinese hamster. The cytotoxic effect denoting MTT assay has shown an IC50 value of 7.56 μM CE, where 50% proliferation inhibition occurs. The oxidative stress caused by CE was confirmed based on GSH depletion induced cell death, conspicuously absent in N-acetylcysteine (GSH precursor) pretreated cells...
September 15, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/28904242/the-g-quadruplex-dna-stabilizing-drug-pyridostatin-promotes-dna-damage-and-downregulates-transcription-of-brca1-in-neurons
#5
Jose F Moruno-Manchon, Edward C Koellhoffer, Jayakrishnan Gopakumar, Shashank Hambarde, Nayun Kim, Louise D McCullough, Andrey S Tsvetkov
The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double-strand breaks (DSBs) in cultured neurons...
September 12, 2017: Aging
https://www.readbyqxmd.com/read/28900015/structure-and-function-of-pif1-helicase
#6
REVIEW
Alicia K Byrd, Kevin D Raney
Pif1 family helicases have multiple roles in the maintenance of nuclear and mitochondrial DNA in eukaryotes. Saccharomyces cerevisiae Pif1 is involved in replication through barriers to replication, such as G-quadruplexes and protein blocks, and reduces genetic instability at these sites. Another Pif1 family helicase in S. cerevisiae, Rrm3, assists in fork progression through replication fork barriers at the rDNA locus and tRNA genes. ScPif1 (Saccharomyces cerevisiae Pif1) also negatively regulates telomerase, facilitates Okazaki fragment processing, and acts with polymerase δ in break-induced repair...
September 12, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28890386/co-targeting-c-met-and-dna-double-strand-breaks-dsbs-therapeutic-strategies-in-brca-mutated-gastric-carcinomas
#7
REVIEW
Chrysovalantou Mihailidou, Michalis V Karamouzis, Dimitrios Schizas, Athanasios G Papavassiliou
Gastric cancer (GC) is a threatening malignancy characterized by heterogeneity. Current therapies use DNA damaging agents, for example, chemotherapeutic agents and ionizing radiation (IR). However, a significant portion of GC patients develops therapeutic resistance to DNA damage response (DDR) - inducing agents. An important mechanism is the stimulation of the c-MET RTK, which is a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), which facilitates cell survival by boosting DNA damage repair pathways and via escaping cell cycle arrest...
September 7, 2017: Biochimie
https://www.readbyqxmd.com/read/28877996/blm-and-slx4-play-opposing-roles-in-recombination-dependent-replication-at-human-telomeres
#8
Alexander P Sobinoff, Joshua Am Allen, Axel A Neumann, Sile F Yang, Monica E Walsh, Jeremy D Henson, Roger R Reddel, Hilda A Pickett
Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA...
September 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28877255/characterization-of-the-microdna-through-the-response-to-chemotherapeutics-in-lymphoblastoid-cell-lines
#9
Pamela Mehanna, Vincent Gagné, Mathieu Lajoie, Jean-François Spinella, Pascal St-Onge, Daniel Sinnett, Ivan Brukner, Maja Krajinovic
Recently, a new class of extrachromosomal circular DNA, called microDNA, was identified. They are on average 100 to 400 bp long and are derived from unique non-repetitive genomic regions with high gene density. MicroDNAs are thought to arise from DNA breaks associated with RNA metabolism or replication slippage. Given the paucity of information on this entirely novel phenomenon, we aimed to get an additional insight into microDNA features by performing the microDNA analysis in 20 independent human lymphoblastoid cell lines (LCLs) prior and after treatment with chemotherapeutic drugs...
2017: PloS One
https://www.readbyqxmd.com/read/28870132/differential-modes-of-photosensitisation-in-cancer-cells-by-berberine-and-coralyne
#10
Rahul Bhattacharyya, Bhaskar Saha, Mrityunjaya Tyagi, Sandip K Bandyopadhyay, Birija Sankar Patro, Subrata Chattopadhyay
In this study, we demonstrated that the cytotoxicity of the protoberberine alkaloids such as coralyne, berberine and jatrorrhizine to several human cancer cell lines can be improved significantly in combination with UVA exposure. However, the phototoxic property of coralyne was much higher than that of the other two alkaloids. The combination of coralyne and UVA (designated as CUVA) induced oxygen-independent cytotoxicity in the human lung cancer A549 cells by producing more lethal DNA double-strand breaks, and the effect was mediated via the replication machinery...
September 5, 2017: Free Radical Research
https://www.readbyqxmd.com/read/28844237/genotoxicity-testing-comparison-of-the-%C3%AE-h2ax-focus-assay-with-the-alkaline-and-neutral-comet-assays
#11
COMPARATIVE STUDY
Teodora Nikolova, Federico Marini, Bernd Kaina
Genotoxicity testing relies on the quantitative measurement of adverse effects, such as chromosome aberrations, micronuclei, and mutations, resulting from primary DNA damage. Ideally, assays will detect DNA damage and cellular responses with high sensitivity, reliability, and throughput. Several novel genotoxicity assays may fulfill these requirements, including the comet assay and the more recently developed γH2AX assay. Although they are thought to be specific for genotoxicants, a systematic comparison of the assays has not yet been undertaken...
October 2017: Mutation Research
https://www.readbyqxmd.com/read/28840551/role-of-protein-linked-dna-breaks-in-cancer
#12
Walaa R Allam, Mohamed E Ashour, Amr A Waly, Sherif El-Khamisy
Topoisomerases are a group of specialized enzymes that function to maintain DNA topology by introducing transient DNA breaks during transcription and replication. As a result of abortive topoisomerases activity, topoisomerases catalytic intermediates may be trapped on the DNA forming topoisomerase cleavage complexes (Topcc). Topoisomerases trapping on the DNA is the mode of action of several anticancer drugs, it lead to formation of protein linked DAN breaks (PDBs). PDBs are now considered as one of the most dangerous forms of endogenous DNA damage and a major threat to genomic stability...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28837865/valproic-acid-sensitizes-breast-cancer-cells-to-hydroxyurea-through-inhibiting-rpa2-hyperphosphorylation-mediated-dna-repair-pathway
#13
Youjia Tian, Guochao Liu, Hui Wang, Zhujun Tian, Zuchao Cai, Fengmei Zhang, Yue Luo, Shue Wang, Gongshe Guo, Xiaowei Wang, Simon Powell, Zhihui Feng
It was reported that valproic acid (VPA, a histone deacetylase inhibitor) can sensitize cancer cells to hydroxyurea (HU, a ribonucleotide reductase inhibitor) for chemotherapy, although the mechanism of VPA-induced HU sensitization is unclear. In this study, we systematically characterized VPA-induced HU sensitization of breast cancer cells. Multiple breast cancer cell models were employed to investigate whether the safe concentration of 0.5mM VPA and 2mM HU can result in DNA double-strand breaks (DSBs) and impact cell survival...
August 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28827409/genomic-and-functional-integrity-of-the-hematopoietic-system-requires-tolerance-of-oxidative-dna-lesions
#14
Ana Martín-Pardillos, Anastasia Tsaalbi-Shtylik, Si Chen, Seka Lazare, Ronald P van Os, Albertina Dethmers-Ausema, Nima Borhan Fakouri, Matthias Bosshard, Rossana Aprigliano, Barbara van Loon, Daniela C F Salvatori, Keiji Hashimoto, Celia Dingemanse-van der Spek, Masaaki Moriya, Lene Juel Rasmussen, Gerald de Haan, Marc H G P Raaijmakers, Niels de Wind
Endogenous DNA damage is causally associated with the functional decline and transformation of stem cells that characterize ageing. DNA lesions that have escaped DNA repair can induce replication stress and genomic breaks that induce senescence and apoptosis. It is not clear how stem and proliferating cells cope with accumulating endogenous DNA lesions, and how these ultimately affect the physiology of cells and tissues. Here we have addressed these questions by investigating the hematopoietic system of mice deficient for Rev1, a core factor in DNA translesion synthesis (TLS), the post-replicative bypass of damaged nucleotides...
August 21, 2017: Blood
https://www.readbyqxmd.com/read/28821455/rnase-hii-saves-rnha-mutant-escherichia-coli-from-r-loop-associated-chromosomal-fragmentation
#15
Elena A Kouzminova, Farid F Kadyrov, Andrei Kuzminov
The rnhAB mutant Escherichia coli, deficient in two RNase H enzymes that remove both R-loops and incorporated ribonucleotides (rNs) from DNA, grow slowly, suggesting accumulation of rN-containing DNA lesions (R-lesions). We report that the rnhAB mutants have reduced viability, form filaments with abnormal nucleoids, induce SOS, and fragment their chromosome, revealing replication and/or segregation stress. R-loops are known to interfere with replication forks, and sensitivity of the double rnhAB mutants to translation inhibition points to R-loops as precursors for R-lesions...
August 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28819201/linker-histone-h1-prevents-r-loop-accumulation-and-genome-instability-in-heterochromatin
#16
Aleix Bayona-Feliu, Anna Casas-Lamesa, Oscar Reina, Jordi Bernués, Fernando Azorín
Linker histone H1 is an important structural component of chromatin that stabilizes the nucleosome and compacts the nucleofilament into higher-order structures. The biology of histone H1 remains, however, poorly understood. Here we show that Drosophila histone H1 (dH1) prevents genome instability as indicated by the increased γH2Av (H2AvS137P) content and the high incidence of DNA breaks and sister-chromatid exchanges observed in dH1-depleted cells. Increased γH2Av occurs preferentially at heterochromatic elements, which are upregulated upon dH1 depletion, and is due to the abnormal accumulation of DNA:RNA hybrids (R-loops)...
August 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28819025/mre11-promotes-tumorigenesis-by-facilitating-resistance-to-oncogene-induced-replication-stress
#17
Elizabeth Spehalski, Kayla M Capper, Cheryl J Smith, Mary J Morgan, Maria Dinkelmann, Jeffrey Buis, JoAnn M Sekiguchi, David O Ferguson
Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double strand breaks where it functions in repair and triggers cell cycle checkpoints via activation of the ataxia-telangiectasia mutated (ATM) kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28817615/genotoxic-effects-of-roundup-full-ii%C3%A2-on-lymphocytes-of-chaetophractus-villosus-xenarthra-mammalia-in-vitro-studies
#18
Juan Pablo Luaces, Luis Francisco Rossi, Mónica Gabriela Chirino, Melanie Browne, María Susana Merani, Marta Dolores Mudry
In Argentina, Chaetophractus villosus has a wide distribution that overlaps with agricultural areas where soybean is the predominant crop. In such areas the pesticide Roundup Full II® (RU) is widely applied. The genotoxic effect of its active ingredient glyphosate (RU is 66.2% glyphosate) on the peripheral blood lymphocytes of C. villosus was tested over a range of concentrations (280, 420, 560, 1120 μmol/L). Culture medium without glyphosate served as negative control, while medium containing mitomycin C served as positive control...
2017: PloS One
https://www.readbyqxmd.com/read/28811464/the-origin-of-a-primordial-genome-through-spontaneous-symmetry-breaking
#19
Nobuto Takeuchi, Paulien Hogeweg, Kunihiko Kaneko
The heredity of a cell is provided by a small number of non-catalytic templates-the genome. How did genomes originate? Here, we demonstrate the possibility that genome-like molecules arise from symmetry breaking between complementary strands of self-replicating molecules. Our model assumes a population of protocells, each containing a population of self-replicating catalytic molecules. The protocells evolve towards maximising the catalytic activities of the molecules to increase their growth rates. Conversely, the molecules evolve towards minimising their catalytic activities to increase their intracellular relative fitness...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28802254/tdp1-is-critical-for-the-repair-of-dna-breaks-induced-by-sapacitabine-a-nucleoside-also-targeting-atm-and-brca-deficient-tumors
#20
Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N Rajapakse, Shar-Yin N Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier
2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes non-phosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1-/- DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC...
August 11, 2017: Molecular Cancer Therapeutics
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