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DNA repair

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https://www.readbyqxmd.com/read/28738540/regulatory-players-of-dna-damage-repair-mechanisms-role-in-cancer-chemoresistance
#1
REVIEW
Kunnathur Murugesan Sakthivel, Sreedharan Hariharan
DNA damaging agents are most common in chemotherapeutic molecules that act against cancer. However, cancer cells possess inherent biological features to overcome DNA damages by activating various distinct repair mechanisms and pathways. Importantly, various oncogenes, cancer stem cells (CSCs), hypoxic environment, transcription factors and bystander signaling that are activated in the cancer cells influence DNA repair, thereby effectively repairing the DNA damage. Repaired cancer cells often become more resistance to further therapy and results in disease recurrence...
July 20, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28738082/short-term-sleep-deprivation-leads-to-decreased-systemic-redox-metabolites-and-altered-epigenetic-status
#2
Malav S Trivedi, Dana Holger, Anh Tuyet Bui, Travis J A Craddock, Jaime L Tartar
Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels...
2017: PloS One
https://www.readbyqxmd.com/read/28737741/rapidly-inducible-cas9-and-dsb-ddpcr-to-probe-editing-kinetics
#3
John C Rose, Jason J Stephany, William J Valente, Bridget M Trevillian, Ha V Dang, Jason H Bielas, Dustin J Maly, Douglas M Fowler
We developed a chemically inducible Cas9 (ciCas9) and a droplet digital PCR assay for double-strand breaks (DSB-ddPCR) to investigate the kinetics of Cas9-mediated generation and repair of DSBs in cells. ciCas9 is a rapidly activated, single-component Cas9 variant engineered by replacing the protein's REC2 domain with the BCL-xL protein and fusing an interacting BH3 peptide to the C terminus. ciCas9 can be tunably activated by a compound that disrupts the BCL-xL-BH3 interaction within minutes. DSB-ddPCR demonstrates time-resolved, highly quantitative, and targeted measurement of DSBs...
July 24, 2017: Nature Methods
https://www.readbyqxmd.com/read/28737709/regulation-and-modulation-of-human-dna-polymerase-%C3%AE-activity-and-function
#4
REVIEW
Marietta Y W T Lee, Xiaoxiao Wang, Sufang Zhang, Zhongtao Zhang, Ernest Y C Lee
This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair...
July 24, 2017: Genes
https://www.readbyqxmd.com/read/28735897/radx-promotes-genome-stability-and-modulates-chemosensitivity-by-regulating-rad51-at-replication-forks
#5
Huzefa Dungrawala, Kamakoti P Bhat, Rémy Le Meur, Walter J Chazin, Xia Ding, Shyam K Sharan, Sarah R Wessel, Aditya A Sathe, Runxiang Zhao, David Cortez
RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks...
July 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28735743/exposure-to-meat-derived-carcinogens-and-bulky-dna-adduct-levels-in-normal-appearing-colon-mucosa
#6
Vikki Ho, Vanessa Brunetti, Sarah Peacock, Thomas E Massey, Roger W L Godschalk, Frederik J van Schooten, Janet E Ashbury, Stephen J Vanner, Will D King
INTRODUCTION: Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. METHODS: Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using (32)P-postlabelling among 202 patients undergoing a screening colonoscopy...
September 2017: Mutation Research
https://www.readbyqxmd.com/read/28735741/apigenin-prevents-ultraviolet-b-radiation-induced-cyclobutane-pyrimidine-dimers-formation-in-human-dermal-fibroblasts
#7
S Mary Britto, D Shanthakumari, B Agilan, T Radhiga, G Kanimozhi, N Rajendra Prasad
Exposure to solar ultraviolet-B (UVB) radiation leads to the formation of cyclobutane pyrimidine dimers (CPDs). We investigated the protective effect of apigenin against UVB-induced CPDs formation in human dermal fibroblasts cells (HDFa). For this purpose, HDFa cells were treated with apigenin (15μM) prior to UVB irradiation (20mJ/cm(2)); DNA damage and subsequent molecular end points were observed. Exposure to UVB radiation increased significant CPDs formation in HDFa cells and the frequencies of CPDs were reduced by treatment with apigenin (15μM)...
September 2017: Mutation Research
https://www.readbyqxmd.com/read/28735739/genome-wide-bisulfite-sensitivity-profiling-of-yeast-suggests-bisulfite-inhibits-transcription
#8
Romulo Segovia, Veena Mathew, Annie S Tam, Peter C Stirling
Bisulfite, in the form of sodium bisulfite or metabisulfite, is used commercially as a food preservative. Bisulfite is used in the laboratory as a single-stranded DNA mutagen in epigenomic analyses of DNA methylation. Recently it has also been used on whole yeast cells to induce mutations in exposed single-stranded regions in vivo. To understand the effects of bisulfite on live cells we conducted a genome-wide screen for bisulfite sensitive mutants in yeast. Screening the deletion mutant array, and collections of essential gene mutants we define a genetic network of bisulfite sensitive mutants...
September 2017: Mutation Research
https://www.readbyqxmd.com/read/28735458/the-efficacy-of-lapatinib-and-nilotinib-in-combination-with-radiation-therapy-in-a-model-of-nf2-associated-peripheral-schwannoma
#9
Iddo Paldor, Sara Abbadi, Nicolas Bonne, Xiaobu Ye, Fausto J Rodriguez, David Rowshanshad, MariaLisa Itzoe, Veronica Vigilar, Marco Giovannini, Henry Brem, Jaishri O Blakeley, Betty M Tyler
Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 (-/-)) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models...
July 22, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28735042/improved-selectivity-and-cytotoxic-effects-of-irinotecan-via-liposomal-delivery-a-comparative-study-on-hs68-and-hela-cells
#10
Ana Casadó, Margarita Mora, M Lluïsa Sagristá, Santi Rello-Varona, Pilar Acedo, Juan Carlos Stockert, Magdalena Cañete, Angeles Villanueva
Irinotecan (CPT-11) is an effective chemotherapeutic agent widely used to treat different cancers. Otherwise, the liposomal delivery of anti-tumor agents has been shown to be a promising strategy. The aim of this study has been to analyze the effect of liposomal CPT-11 (CPT-11lip) on two human cell lines (Hs68 and HeLa) to establish the suitability of this CPT-11 nanocarrier. We have demonstrated the highest uptake of CPT-11lip in comparison with that of CPT-11sol, in lactate buffer, and that CPT-11lip was internalized in the cells through an endocytic process whereas CPT-11sol does so by passive diffusion...
July 19, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28734759/nivolumab-in-patients-with-metastatic-dna-mismatch-repair-deficient-or-microsatellite-instability-high-colorectal-cancer-checkmate-142-an-open-label-multicentre-phase-2-study
#11
Michael J Overman, Ray McDermott, Joseph L Leach, Sara Lonardi, Heinz-Josef Lenz, Michael A Morse, Jayesh Desai, Andrew Hill, Michael Axelson, Rebecca A Moss, Monica V Goldberg, Z Alexander Cao, Jean-Marie Ledeine, Gregory A Maglinte, Scott Kopetz, Thierry André
BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer...
July 19, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28733611/integrin-%C3%AE-6%C3%AE-4-upregulates-amphiregulin-and-epiregulin-through-base-excision-repair-mediated-dna-demethylation-and-promotes-genome-wide-dna-hypomethylation
#12
Brittany L Carpenter, Jinpeng Liu, Lei Qi, Chi Wang, Kathleen L O'Connor
Aberrant DNA methylation patterns are a common theme across all cancer types. Specific DNA demethylation of regulatory sequences can result in upregulation of genes that are critical for tumor development and progression. Integrin α6β4 is highly expressed in pancreatic carcinoma and contributes to cancer progression, in part, through the specific DNA demethylation and upregulation of epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG). Whole genome bisulfite sequencing (WGBS) revealed that integrin α6β4 signaling promotes an overall hypomethylated state and site specific DNA demethylation of enhancer elements within the proximal promoters of AREG and EREG...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28733409/using-pulsed-field-gel-electrophoresis-to-analyze-schizosaccharomyces-pombe-chromosomes-and-chromosomal-elements
#13
Chen-Chun Pai, Carol Walker, Timothy Humphrey
Pulsed field gel electrophoresis (PFGE) uses alternatively oriented pulsed electrical fields to separate large DNA molecules. Here, we describe PFGE protocols and conditions for separating and visualizing chromosomes between 0.5 and 6 Mb (optimal for analyzing the endogenous fission yeast chromosomes of 5.7, 4.6, and 3.5 Mb), and for shorter chromosomal elements of between 50 and 600 kb, such as the 530 kb Ch(16) minichromosome. In addition to determining chromosome size, this technique has a wide range of applications, including determining whether DNA replication or repair is complete, defining the molecular karyotype of cells, analyzing chromosomal rearrangements, assigning genes or constructs to particular chromosomes, and isolating DNA from specific chromosomes...
July 21, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/28733408/dna-double-strand-break-repair-assay
#14
Chen-Chun Pai, Elizabeth Blaikley, Timothy C Humphrey
DNA double-strand breaks (DSBs), arising during normal DNA metabolism or following exposure to mutagenic agents such as ionizing radiation can lead to chromosomal rearrangements and genome instability, and are potentially lethal if unrepaired. Therefore, understanding the mechanisms of DSB repair and misrepair, and identifying the factors involved in these processes is of biological as well as medical interest. Here we describe a DSB assay in Schizosaccharomyces pombe that can be used to identify and quantify different repair, misrepair, and failed repair events resulting from a site-specific DSB within the context of a nonessential minichromosome, Ch(16) This assay can be used to determine the contribution of most genes or genetic backgrounds to DSB repair and genome stability, and can also provide mechanistic insights into their function...
July 21, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/28733402/analysis-of-dna-metabolism-in-fission-yeast
#15
Francisco Antequera, Timothy C Humphrey
The fission yeast Schizosaccharomyces pombe is an excellent model organism to study DNA metabolism, in which the DNA replication and repair mechanisms are evolutionarily conserved. In this introduction we describe a range of methods commonly used to study aspects of DNA metabolism in fission yeast, focusing on approaches used for the analysis of genome stability, DNA replication, and DNA repair. We describe the use of a minichromosome, Ch(16), for monitoring different aspects of genome stability. We introduce two-dimensional gel electrophoresis and immunofluorescent visualization of combed DNA molecules for the analysis of DNA replication...
July 21, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/28733204/the-polymorphism-xrcc1-arg194trp-and-8-hydroxydeoxyguanosine-increased-susceptibility-to-arsenic-related-renal-cell-carcinoma
#16
Yu-Mei Hsueh, Ying-Chin Lin, Wei-Jen Chen, Chao-Yuan Huang, Horng-Sheng Shiue, Yeong-Shiau Pu, Chi-Hung Chen, Chien-Tien Su
This study was designed to explore the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8-OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age- and sex-matched controls from a hospital-based pool. Image-guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification...
July 18, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28732771/application-of-the-gene-editing-tool-crispr-cas9-for-treating-neurodegenerative-diseases
#17
REVIEW
Nivya Kolli, Ming Lu, Panchanan Maiti, Julien Rossignol, Gary Leo Dunbar
Increased accumulation of transcribed protein from the damaged DNA and reduced DNA repair capability contributes to numerous neurological diseases for which effective treatments are lacking. Gene editing techniques provide new hope for replacing defective genes and DNA associated with neurological diseases. With advancements in using such editing tools as zinc finger nucleases (ZFNs), meganucleases, and transcription activator-like effector nucleases (TALENs), etc., scientists are able to design DNA-binding proteins, which can make precise double-strand breaks (DSBs) at the target DNA...
July 18, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28732447/dna-polymerase-%C3%AE-active-site-favors-a-mutagenic-mispair-between-the-enol-form-of-deoxyguanosine-triphosphate-substrate-and-the-keto-form-of-thymidine-template-a-free-energy-perturbation-study
#18
Sergey N Maximoff, Shina C L Kamerlin, Jan Florian
Human DNA polymerase λ is an intermediate fidelity member of the X family, which plays a role in DNA repair. Recent X-ray diffraction structures of a ternary complex of a loop-deletion mutant of polymerase λ, a deoxyguanosine triphosphate analog and a gapped DNA show that guanine and thymine form a mutagenic mispair with an unexpected Watson-Crick-like geometry rather than a wobble geometry. Hence, there is an intriguing possibility that either thymine in the DNA or guanine in the deoxyguanosine triphosphate analog may spend a substantial fraction of time in a deprotonated or enol form (both are minor species in aqueous solution) in the active site of the polymerase λ mutant...
July 21, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28732364/a-novel-heterozygous-germline-deletion-in-msh2-gene-in-a-five-generation-chinese-family-with-lynch-syndrome
#19
Bin Wu, Wuyang Ji, Shengran Liang, Chao Ling, Yan You, Lai Xu, Min-Er Zhong, Yi Xiao, Hui-Zhong Qiu, Jun-Yang Lu, Santasree Banerjee
Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6and PMS2. Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five generation Chinese family with LS clinically diagnosed according to the Amsterdam II criteria...
July 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28732309/zebularine-induces-replication-dependent-double-strand-breaks-which-are-preferentially-repaired-by-homologous-recombination
#20
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
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