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https://www.readbyqxmd.com/read/27923110/impact-of-oligonucleotide-structure-chemistry-and-delivery-method-on-in-vitro-cytotoxicity
#1
Maja M Janas, Yongfeng Jiang, Mark K Schlegel, Scott Waldron, Satya Kuchimanchi, Scott A Barros
Single-stranded (ss) 2'-fluoro (2'-F)-modified oligonucleotides (ONs) with a full phosphorothioate (PS) backbone have been reported to be cytotoxic and cause DNA double-strand breaks (DSBs) when transfected into HeLa cells. However, the molecular determinants of these effects have not been fully explored. In this study, we investigated the impact of ON structure, chemistry, delivery method, and cell type on in vitro cytotoxicity and DSBs. We found that ss PS-ONs were more cytotoxic than double-stranded (ds) PS-ONs, irrespective of the 2'-ribose chemistry, inclusive of the 2'-F modification...
December 6, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27922819/early-age-decline-in-dna-repair-capacity-in-the-liver-in-depth-profile-of-differential-gene-expression
#2
Avital Guedj, Anat Geiger-Maor, Eithan Galun, Hagai Amsalem, Jacob Rachmilewitz
Aging is associated with progressive decline in cell function and with increased damage to macromolecular components. DNA damage, in the form of double-strand breaks (DSBs), increases with age and in turn, contributes to the aging process and age-related diseases. DNA strand breaks triggers a set of highly orchestrated signaling events known as the DNA damage response (DDR), which coordinates DNA repair. However, whether the accumulation of DNA damage with age is a result of decreased repair capacity, remains to be determined...
November 30, 2016: Aging
https://www.readbyqxmd.com/read/27922110/%C3%AE-h2ax-53bp1-pkap-1-foci-and-their-linear-tracks-induced-by-in-vitro-exposure-to-radon-and-its-progeny-in-human-peripheral-blood-lymphocytes
#3
Defang Ding, Yaping Zhang, Jing Wang, Xufei Wang, Dunhuang Fan, Linfeng He, Xuxia Zhang, Yun Gao, Qiang Li, Honghong Chen
The biodosimetric information is critical for evaluating the human health hazards caused by radon and its progeny. Here, we demonstrated that the formation of phosphorylated histone variant H2AX (γ-H2AX), p53-binding protein 1 (53BP1) and phosphorylated KRAB-associated protein 1 (pKAP-1) foci and their linear tracks in human peripheral blood lymphocytes (HPBLs) in vitro exposed to radon and its progeny were dependent on the cumulative absorbed dose of radon exposure but was unrelated to the concentration of radon...
December 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27922005/wrn-regulates-pathway-choice-between-classical-and-alternative-non-homologous-end-joining
#4
Raghavendra A Shamanna, Huiming Lu, Jessica K de Freitas, Jane Tian, Deborah L Croteau, Vilhelm A Bohr
Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27915381/regulation-of-non-homologous-end-joining-via-post-translational-modifications-of-components-of-the-ligation-step
#5
REVIEW
Kristína Durdíková, Miroslav Chovanec
DNA double-strand breaks are the most serious type of DNA damage and non-homologous end joining (NHEJ) is an important pathway for their repair. In Saccharomyces cerevisiae, three complexes mediate the canonical NHEJ pathway, Ku (Ku70/Ku80), MRX (Mre11/Rad50/Xrs2) and DNA ligase IV (Dnl4/Lif1). Mammalian NHEJ is more complex, primarily as a consequence of the fact that more factors are involved in the process, and also because higher chromatin organization and more complex regulatory networks exist in mammals...
December 3, 2016: Current Genetics
https://www.readbyqxmd.com/read/27914716/replication-stalling-and-dna-microsatellite-instability
#6
M Leffak, R Gadgil, J Barthelemy, T Lewis
Microsatellites are short, tandemly repeated DNA motifs of 1-6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively, these repeats comprise approximately 3% of the human genome Subramanian et al. (2003), Lander and Lander (2001) [1,2], and represent a large reservoir of loci highly prone to mutations Sun et al. (2012), Ellegren (2004) [3,4] that contribute to human evolution and disease. Microsatellites are known to stall and reverse replication forks in model systems Pelletier et al...
November 22, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27913567/drug-repositioning-screens-identify-triamterene-as-a-selective-drug-for-the-treatment-of-dna-mismatch-repair-deficient-cells
#7
Delphine Guillotin, Philip Austin, Rumena Begum, Marta O Freitas, Ashirwad Merve, Tim Brend, Susan C Short, Silvia Marino, Sarah A Martin
PURPOSE: The DNA Mismatch repair (MMR) pathway is required for the maintenance of genome stability. Unsurprisingly, mutations in MMR genes occur in a wide range of different cancers. Studies thus far have largely focused on specific tumor types or MMR mutations, however it is becoming increasingly clear that a therapy targeting MMR-deficiency in general would be clinically very beneficial. EXPERIMENTAL DESIGN: Based on a drug-repositioning approach, we screened a large panel of cell lines with various MMR deficiencies from a range of different tumor types with a compound drug library of previously approved drugs...
December 2, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27911848/global-analysis-of-genomic-instability-caused-by-dna-replication-stress-in-saccharomyces-cerevisiae
#8
Dao-Qiong Zheng, Ke Zhang, Xue-Chang Wu, Piotr A Mieczkowski, Thomas D Petes
DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the low-polymerase strains to repair double-stranded DNA breaks (DSBs)...
November 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27911745/the-role-of-epigenetic-mechanisms-in-the-regulation-of-gene-expression-in-the-nervous-system
#9
Justyna Cholewa-Waclaw, Adrian Bird, Melanie von Schimmelmann, Anne Schaefer, Huimei Yu, Hongjun Song, Ram Madabhushi, Li-Huei Tsai
Neuroepigenetics is a newly emerging field in neurobiology that addresses the epigenetic mechanism of gene expression regulation in various postmitotic neurons, both over time and in response to environmental stimuli. In addition to its fundamental contribution to our understanding of basic neuronal physiology, alterations in these neuroepigenetic mechanisms have been recently linked to numerous neurodevelopmental, psychiatric, and neurodegenerative disorders. This article provides a selective review of the role of DNA and histone modifications in neuronal signal-induced gene expression regulation, plasticity, and survival and how targeting these mechanisms could advance the development of future therapies...
November 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27911443/transient-mitochondrial-dna-double-strand-breaks-in-mice-cause-accelerated-aging-phenotypes-in-a-ros-dependent-but-p53-p21-independent-manner
#10
Milena Pinto, Alicia M Pickrell, Xiao Wang, Sandra R Bacman, Aixin Yu, Aline Hida, Lloye M Dillon, Paul D Morton, Thomas R Malek, Siôn L Williams, Carlos T Moraes
We observed that the transient induction of mtDNA double strand breaks (DSBs) in cultured cells led to activation of cell cycle arrest proteins (p21/p53 pathway) and decreased cell growth, mediated through reactive oxygen species (ROS). To investigate this process in vivo we developed a mouse model where we could transiently induce mtDNA DSBs ubiquitously. This transient mtDNA damage in mice caused an accelerated aging phenotype, preferentially affecting proliferating tissues. One of the earliest phenotypes was accelerated thymus shrinkage by apoptosis and differentiation into adipose tissue, mimicking age-related thymic involution...
December 2, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27909234/a-high-throughput-screening-strategy-for-development-of-rnf8-ubc13-protein-protein-interaction-inhibitors
#11
Elisabeth Weber, Ina Rothenaigner, Stefanie Brandner, Kamyar Hadian, Kenji Schorpp
The ubiquitin-proteasome system plays an essential role in a broad range of cellular signaling pathways. Ubiquitination is a posttranslational protein modification that involves the action of an enzymatic cascade (E1, E2, and E3 enzymes) for the covalent attachment of ubiquitin to target proteins. The emerging knowledge of the molecular mechanisms and correlation of deregulation of the ubiquitin system in human diseases is uncovering new opportunities for therapeutics development. The E3 ligase RNF8 acts in cooperation with the heterodimeric E2 enzyme Ubc13/Uev1a to generate ubiquitin conjugates at the sides of DNA double-strand breaks, and recent findings suggest RNF8 as a potential therapeutic target for the treatment of breast cancer...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27907109/loss-of-h3k9me3-correlates-with-atm-activation-and-histone-h2ax-phosphorylation-deficiencies-in-hutchinson-gilford-progeria-syndrome
#12
Haoyue Zhang, Linlin Sun, Kun Wang, Di Wu, Mason Trappio, Celeste Witting, Kan Cao
Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour...
2016: PloS One
https://www.readbyqxmd.com/read/27903905/human-mlh1-suppresses-the-insertion-of-telomeric-sequences-at-intra-chromosomal-sites-in-telomerase-expressing-cells
#13
Pingping Jia, Megan Chastain, Ying Zou, Chengtao Her, Weihang Chai
Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27903895/protein-dynamics-of-human-rpa-and-rad51-on-ssdna-during-assembly-and-disassembly-of-the-rad51-filament
#14
Chu Jian Ma, Bryan Gibb, YoungHo Kwon, Patrick Sung, Eric C Greene
Homologous recombination (HR) is a crucial pathway for double-stranded DNA break (DSB) repair. During the early stages of HR, the newly generated DSB ends are processed to yield long single-stranded DNA (ssDNA) overhangs, which are quickly bound by replication protein A (RPA). RPA is then replaced by the DNA recombinase Rad51, which forms extended helical filaments on the ssDNA. The resulting nucleoprotein filament, known as the presynaptic complex, is responsible for pairing the ssDNA with homologous double-stranded DNA (dsDNA), which serves as the template to guide DSB repair...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27903656/yeast-hmo1-linker-histone-reinvented
#15
REVIEW
Arvind Panday, Anne Grove
Eukaryotic genomes are packaged in chromatin. The higher-order organization of nucleosome core particles is controlled by the association of the intervening linker DNA with either the linker histone H1 or high mobility group box (HMGB) proteins. While H1 is thought to stabilize the nucleosome by preventing DNA unwrapping, the DNA bending imposed by HMGB may propagate to the nucleosome to destabilize chromatin. For metazoan H1, chromatin compaction requires its lysine-rich C-terminal domain, a domain that is buried between globular domains in the previously characterized yeast Saccharomyces cerevisiae linker histone Hho1p...
March 2017: Microbiology and Molecular Biology Reviews: MMBR
https://www.readbyqxmd.com/read/27903633/an-e2-guided-e3-screen-identifies-the-rnf17-ube2u-pair-as-regulator-of-the-riddle-syndrome-protein-rnf168
#16
Yingying Guo, Liwei An, Hoi-Man Ng, Shirley M H Sy, Michael S Y Huen
Protein ubiquitination has emerged as pivotal regulatory reactions that promote cellular responses to DNA damage. With a goal to delineate the DNA damage signal transduction cascade, we systematically analysed the human E2 ubiquitin and ubiquitin-like conjugating enzymes for their ability to mobilise the DNA damage marker 53BP1 onto IR-induced DNA double-strand breaks (DSBs). RNAi-based screen identified UBE2U as a candidate regulator of chromatin responses at DSBs. Further mining of the UBE2U interactome uncovered its cognate E3 RNF17 as a novel factor that, via the Riddle syndrome protein RNF168, enforces DNA damage responses...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27903196/the-impact-of-cobalt-60-source-age-on-biologically-effective-dose-in-high-dose-functional-gamma-knife-radiosurgery
#17
Benjamin H Kann, James B Yu, John M Stahl, James E Bond, Christopher Loiselle, Veronica L Chiang, Ranjit S Bindra, Jason L Gerrard, David J Carlson
OBJECTIVE Functional Gamma Knife radiosurgery (GKRS) procedures have been increasingly used for treating patients with tremor, trigeminal neuralgia (TN), and refractory obsessive-compulsive disorder. Although its rates of toxicity are low, GKRS has been associated with some, if low, risks for serious sequelae, including hemiparesis and even death. Anecdotal reports have suggested that even with a standardized prescription dose, rates of functional GKRS toxicity increase after replacement of an old cobalt-60 source with a new source...
December 2016: Journal of Neurosurgery
https://www.readbyqxmd.com/read/27902462/the-synthetic-lethal-killing-of-rad54b-deficient-colorectal-cancer-cells-by-parp1-inhibition-is-enhanced-with-sod1-inhibition
#18
Erin N McAndrew, Chloe C Lepage, Kirk J McManus
Colorectal cancer (CRC) is a leading cause of cancer-related death throughout the world. Despite improved screening efforts, most CRCs are diagnosed at late stages when surgery alone is not curative. Moreover, the low 5-year survival rate (~8-13%) for those living with stage IV CRC highlights the need for better treatment options. Many current chemotherapeutic approaches are non-specific and associated with side effects due to their tendency to target both normal and cancer cells. To address this issue, synthetic lethal (SL) approaches are now being explored in cancer and are defined as the lethal combination of two independently viable mutations/deletions...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27902438/dna-double-strand-break-repair-is-involved-in-desiccation-resistance-of-sinorhizobium-meliloti-but-is-not-essential-for-its-symbiotic-interaction-with-medicago-truncatula
#19
Pierre Dupuy, Benjamin Gourion, Laurent Sauviac, Claude Bruand
The soil bacterium Sinorhizobium meliloti, a nitrogen-fixing symbiont of legume plants, is exposed to numerous stress conditions in nature, some of which cause the formation of harmful DNA double strand breaks (DSB). In particular, the reactive oxygen (ROS) and nitrogen (RNS) species produced during symbiosis, and the desiccation occurring in dry soils, are conditions which induce DSB. Two major systems of DSB repair are known in S. meliloti: homologous recombination (HR) and non-homologous end-joining (NHEJ)...
November 23, 2016: Microbiology
https://www.readbyqxmd.com/read/27900318/templated-sequence-insertion-polymorphisms-in-the-human-genome
#20
REVIEW
Masahiro Onozawa, Peter D Aplan
Templated Sequence Insertion Polymorphism (TSIP) is a recently described form of polymorphism recognized in the human genome, in which a sequence that is templated from a distant genomic region is inserted into the genome, seemingly at random. TSIPs can be grouped into two classes based on nucleotide sequence features at the insertion junctions; Class 1 TSIPs show features of insertions that are mediated via the LINE-1 ORF2 protein, including (1) target-site duplication (TSD), (2) polyadenylation 10-30 nucleotides downstream of a "cryptic" polyadenylation signal, and (3) preference for insertion at a 5'-TTTT/A-3' sequence...
2016: Frontiers in Chemistry
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