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https://www.readbyqxmd.com/read/28817615/genotoxic-effects-of-roundup-full-ii%C3%A2-on-lymphocytes-of-chaetophractus-villosus-xenarthra-mammalia-in-vitro-studies
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28802045/transcription-replication-conflict-orientation-modulates-r-loop-levels-and-activates-distinct-dna-damage-responses
#4
Stephan Hamperl, Michael J Bocek, Joshua C Saldivar, Tomek Swigut, Karlene A Cimprich
Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28792846/nanodosimetric-simulation-of-direct-ion-induced-dna-damage-using-different-chromatin-geometry-models
#5
N T Henthorn, J W Warmenhoven, M Sotiropoulos, R I Mackay, K J Kirkby, M J Merchant
Monte Carlo based simulation has proven useful in investigating the effect of proton-induced DNA damage and the processes through which this damage occurs. Clustering of ionizations within a small volume can be related to DNA damage through the principles of nanodosimetry. For simulation, it is standard to construct a small volume of water and determine spatial clusters. More recently, realistic DNA geometries have been used, tracking energy depositions within DNA backbone volumes. Traditionally a chromatin fiber is built within the simulation and identically replicated throughout a cell nucleus, representing the cell in interphase...
August 9, 2017: Radiation Research
https://www.readbyqxmd.com/read/28790200/chromosome-end-repair-and-genome-stability-in-plasmodium-falciparum
#6
Susannah F Calhoun, Jake Reed, Noah Alexander, Christopher E Mason, Kirk W Deitsch, Laura A Kirkman
The human malaria parasite Plasmodium falciparum replicates within circulating red blood cells, where it is subjected to conditions that frequently cause DNA damage. The repair of DNA double-stranded breaks (DSBs) is thought to rely almost exclusively on homologous recombination (HR), due to a lack of efficient nonhomologous end joining. However, given that the parasite is haploid during this stage of its life cycle, the mechanisms involved in maintaining genome stability are poorly understood. Of particular interest are the subtelomeric regions of the chromosomes, which contain the majority of the multicopy variant antigen-encoding genes responsible for virulence and disease severity...
August 8, 2017: MBio
https://www.readbyqxmd.com/read/28781144/regulation-of-repair-pathway-choice-at-two-ended-dna-double-strand-breaks
#7
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/28779875/paths-from-dna-damage-and-signaling-to-genome-rearrangements-via-homologous-recombination
#8
REVIEW
Jac A Nickoloff
DNA damage is a constant threat to genome integrity. DNA repair and damage signaling networks play a central role maintaining genome stability, suppressing tumorigenesis, and determining tumor response to common cancer chemotherapeutic agents and radiotherapy. DNA double-strand breaks (DSBs) are critical lesions induced by ionizing radiation and when replication forks encounter damage. DSBs can result in mutations and large-scale genome rearrangements reflecting mis-repair by non-homologous end joining or homologous recombination...
July 24, 2017: Mutation Research
https://www.readbyqxmd.com/read/28765330/genome-stability-by-dna-polymerase-%C3%AE-in-neural-progenitors-contributes-to-neuronal-differentiation-in-cortical-development
#9
Kohei Onishi, Akiko Uyeda, Mitsuhiro Shida, Teruyoshi Hirayama, Takeshi Yagi, Nobuhiko Yamamoto, Noriyuki Sugo
DNA repair is crucial for genome stability in the developing cortex, as somatic de novo mutations cause neurological disorders. However, how DNA repair contributes to neuronal development is largely unknown. To address this issue, we studied the spatiotemporal roles of DNA polymerase β (Polβ), a key enzyme in DNA base excision repair (BER) pathway, in the developing cortex using distinct forebrain-specific conditional knockout mice, Emx1-Cre/Polβ(fl/fl) and Nex-Cre/Polβ(fl/fl) mice. Polβ expression was absent in both neural progenitors and postmitotic neurons in Emx1-Cre/Polβ(fl/fl) mice, while only postmitotic neurons lacked Polβ expression in Nex-Cre/Polβ(fl/fl) mice...
August 1, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28760773/alternative-lengthening-of-telomeres-mediated-by-mitotic-dna-synthesis-engages-break-induced-replication-processes
#10
Jaewon Min, Woodring E Wright, Jerry W Shay
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase positive cells and their hTERC knockout derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in S...
July 31, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28754657/recombination-at-subtelomeres-is-regulated-by-physical-distance-double-strand-break-resection-and-chromatin-status
#11
Amandine Batté, Clémentine Brocas, Hélène Bordelet, Antoine Hocher, Myriam Ruault, Adouda Adjiri, Angela Taddei, Karine Dubrana
Homologous recombination (HR) is a conserved mechanism that repairs broken chromosomes via intact homologous sequences. How different genomic, chromatin and subnuclear contexts influence HR efficiency and outcome is poorly understood. We developed an assay to assess HR outcome by gene conversion (GC) and break-induced replication (BIR), and discovered that subtelomeric double-stranded breaks (DSBs) are preferentially repaired by BIR despite the presence of flanking homologous sequences. Overexpression of a silencing-deficient SIR3 mutant led to active grouping of telomeres and specifically increased the GC efficiency between subtelomeres...
July 28, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28733609/suppression-of-hbv-replication-by-the-expression-of-nickase-and-nuclease-dead-cas9
#12
Takeshi Kurihara, Takasuke Fukuhara, Chikako Ono, Satomi Yamamoto, Kentaro Uemura, Toru Okamoto, Masaya Sugiyama, Daisuke Motooka, Shota Nakamura, Masato Ikawa, Masashi Mizokami, Yoshihiko Maehara, Yoshiharu Matsuura
Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28732309/zebularine-induces-replication-dependent-double-strand-breaks-which-are-preferentially-repaired-by-homologous-recombination
#13
Manuel Luis Orta, Nuria Pastor, Estefanía Burgos-Morón, Inmaculada Domínguez, José Manuel Calderón-Montaño, Carlos Huertas Castaño, Miguel López-Lázaro, Thomas Helleday, Santiago Mateos
Zebularine is a second-generation, highly stable hydrophilic inhibitor of DNA methylation with oral bioavailability that preferentially target cancer cells. It acts primarily as a trap for DNA methyl transferases (DNMTs) protein by forming covalent complexes between DNMT protein and zebularine-substrate DNA. It's well documented that replication-blocking DNA lesions can cause replication fork collapse and thereby to the formation of DNA double-strand breaks (DSB). DSB are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death...
July 12, 2017: DNA Repair
https://www.readbyqxmd.com/read/28713155/hypoxia-induces-universal-but-differential-drug-resistance-and-impairs-anticancer-mechanisms-of-5-fluorouracil-in-hepatoma-cells
#14
Jing-Qiu Li, Xian Wu, Lu Gan, Xiang-Liang Yang, Ze-Hong Miao
Hepatocellular carcinoma (HCC) is one of the most refractory cancers. The mechanisms by which hypoxia further aggravates therapeutic responses of advanced HCC to anticancer drugs remain to be clarified. Here, we report that hypoxia (1% O2) caused 2.55-489.7-fold resistance to 6 anticancer drugs (sorafenib, 5-fluorouracil [5-FU], gemcitabine, cisplatin, adriamycin and 6-thioguanine) in 3 HCC cell lines (BEL-7402, HepG2 and SMMC-7721). Among the 6 drugs, sorafenib, the sole one approved for HCC therapy, inhibited proliferation with little influence from hypoxia and displayed the smallest variation among the 3 HCC cell lines tested...
July 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28703879/precarious-maintenance-of-simple-dna-repeats-in-eukaryotes
#15
REVIEW
Alexander J Neil, Jane C Kim, Sergei M Mirkin
In this review, we discuss how two evolutionarily conserved pathways at the interface of DNA replication and repair, template switching and break-induced replication, lead to the deleterious large-scale expansion of trinucleotide DNA repeats that cause numerous hereditary diseases. We highlight that these pathways, which originated in prokaryotes, may be subsequently hijacked to maintain long DNA microsatellites in eukaryotes. We suggest that the negative mutagenic outcomes of these pathways, exemplified by repeat expansion diseases, are likely outweighed by their positive role in maintaining functional repetitive regions of the genome such as telomeres and centromeres...
July 13, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28696814/ddx19-links-mrna-nuclear-export-with-progression-of-transcription-and-replication-and-suppresses-genomic-instability-upon-dna-damage-in-proliferating-cells
#16
Dana Hodroj, Kamar Serhal, Domenico Maiorano
The DEAD-box Helicase 19 (Ddx19) gene codes for an RNA helicase involved in both messenger RNA (mRNA) export from the nucleus into the cytoplasm and in mRNA translation. In unperturbed cells, Ddx19 localizes in the cytoplasm and at the cytoplasmic face of the nuclear pore. Here we review recent findings related to an additional Ddx19 function in the nucleus in resolving RNA:DNA hybrids (R-loops) generated during collision between transcription and replication, and upon DNA damage. Activation of a DNA damage response pathway dependent upon the ATR kinase, a major regulator of replication fork progression, stimulates translocation of the Ddx19 protein from the cytoplasm into the nucleus...
July 11, 2017: Nucleus
https://www.readbyqxmd.com/read/28676700/the-multifaceted-roles-of-parp1-in-dna-repair-and-chromatin-remodelling
#17
REVIEW
Arnab Ray Chaudhuri, André Nussenzweig
Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers...
July 5, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28645381/examining-dna-double-strand-break-repair-in-a-cell-cycle-dependent-manner
#18
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/28631426/hsp90%C3%AE-regulates-atm-and-nbn-functions-in-sensing-and-repair-of-dna-double-strand-breaks
#19
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/28630044/single-molecule-f%C3%A3-rster-resonance-energy-transfer-fret-analysis-discloses-the-dynamics-of-the-dna-topoisomerase-ii-top2-interaction-in-the-presence-of-top2-targeting-agents
#20
Wan-Chen Huang, Chun-Ying Lee, Tao-Shih Hsieh
Topoisomerases play crucial roles in DNA replication, transcription, and recombination. For instance, topoisomerase II (Top2) is critically important for resolving DNA tangles during cell division, and as such, it is a broad anticancer drug target. Top2 regulates DNA topology by transiently breaking one double-stranded DNA molecule (cleavage), allowing a second double strand to pass through the opened DNA gate (opening), and then closing the gate by rejoining the broken ends. Drugs that modulate Top2 catalysis may therefore affect enzymatic activity at several different steps...
July 28, 2017: Journal of Biological Chemistry
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