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Double strand break

Liset de la Fuente Rosales, Sebastien Incerti, Ziad Francis, Mario A Bernal
The use of Monte Carlo (MC) simulations remains a powerful tool to study the biological effects induced by ionizing radiation on living beings. Several MC codes are commonly used in research fields such as nanodosimetry, radiotherapy, radiation protection, and space radiation. This work presents an enhancement of an existing model [1] for radiobiological purposes, to account for the indirect DNA damage induced by ionizing particles. The Geant4-DNA simulation toolkit was used to simulate the physical, pre-chemical, and chemical stages of early DNA damage induced by protons and α-particles...
June 13, 2018: Physica Medica: PM
Rasmus O Bak, Natalia Gomez-Ospina, Matthew H Porteus
Smithies et al. (1985) and Jasin and colleagues (1994) provided proof of concept that homologous recombination (HR) could be applied to the treatment of human disease and that its efficiency could be improved by the induction of double-strand breaks (DSBs). A key advance was the discovery of engineered nucleases, such as zinc-finger nucleases (ZFNs) and transcription activator-like (TAL) effector nucleases (TALENs), that can generate site-specific DSBs. The democratization and widespread use of genome editing was enabled by the discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease system...
June 13, 2018: Trends in Genetics: TIG
Alessandro Repici, Camilla Ciscato, Michael Wallace, Prateek Sharma, Andrea Anderloni, Silvia Carrara, Milena Di Leo, Cesare Hassan
BACKGROUND:  An oral formulation of methylene blue with colonic delivery (MB-MMX) has been developed to increase detection of colorectal polys during colonoscopy. Traditionally, there have been safety concerns regarding DNA damage when methylene blue is exposed to white light. The aim of this study was to evaluate DNA damage in colonic mucosa after MB-MMX chromoendoscopy. METHODS:  This was an open-label phase II safety study to assess for genotoxicity on colorectal biopsies of patients undergoing two sequential colonoscopies before and after an oral dose of 200 mg MB-MMX added to their bowel prep...
June 15, 2018: Endoscopy
Anna Banasiak, John Cassidy, John Colleran
To date, DNA cleavage, caused by cleavage agents, has been monitored mainly by gel and capillary electrophoresis. However, these techniques are time-consuming, non-quantitative and require gel stains. In this work, a novel, simple and, importantly, a quantitative method for monitoring the DNA nuclease activity of potential anti-cancer drugs, at a DNA electrochemical sensor, is presented. The DNA sensors were prepared using thiol-modified oligonucleotides that self-assembled to create a DNA monolayer at gold electrode surfaces...
June 1, 2018: Biosensors & Bioelectronics
Fabrizio Cleri, Fabio Landuzzi, Ralf Blossey
Double strand breaks (DSB) in the DNA backbone are the most lethal type of defect induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the outcomes of damage in nucleosomal DNA, and on its effects on damage repair. We performed microsecond-long molecular dynamics computer simulations of nucleosomes including a DSB at various sites, to characterize the early stages of the evolution of this DNA lesion. The damaged structures are studied by the essential dynamics of DNA and histones, and compared to the intact nucleosome, thus exposing key features of the interactions...
June 14, 2018: PLoS Computational Biology
Patricia Richard, Koichi Ogami, Yaqiong Chen, Shuang Feng, James J Moresco, John R Yates, James L Manley
The RNA helicase Mtr4 is a versatile protein that is a crucial component of several distinct RNA surveillance complexes. Here we describe a novel complex that contains Mtr4, but has a role distinct from any of those previously described. We found that Mtr4 association with the human homolog of fission yeast Nrl1, NRDE-2, defines a novel function for Mtr4 in the DNA damage response (DDR) pathway. We provide biochemical evidence that Mtr4 and NRDE-2 are part of the same complex and show that both proteins play a role in the DDR by maintaining low DNA double-strand break levels...
June 14, 2018: RNA Biology
Martin A White, Benura Azeroglu, Manuel A Lopez-Vernaza, A M Mahedi Hasan, David R F Leach
DNA double-strand break (DSB) repair is critical for cell survival. A diverse range of organisms from bacteria to humans rely on homologous recombination for accurate DSB repair. This requires both coordinate action of the two ends of a DSB and stringent control of the resultant DNA replication to prevent unwarranted DNA amplification and aneuploidy. In Escherichia coli, RecBCD enzyme is responsible for the initial steps of homologous recombination. Previous work has revealed recD mutants to be nuclease defective but recombination proficient...
June 13, 2018: Nucleic Acids Research
Erica K Low, Egil Brudvik, Bradford Mitchell Kuhlman, Paul F Wilson, Graca M Almeida-Porada, Christopher D Porada
Astronauts on missions beyond low-Earth orbit are exposed to a hostile environment in which they are continually bombarded with unique high-energy species of radiation, while in conditions of microgravity (G), which can alter radiation response and immunity. In the present studies, we examined the impact exposing human hematopoietic stem/progenitor cells (HSC) to μG had upon their capacity to repair DNA damage and their ability to generate immune cells critical for mounting an effective anti-tumor response...
June 14, 2018: Stem Cells and Development
Anne Steininger, Grit Ebert, Benjamin V Becker, Chalid Assaf, Markus Möbs, Christian A Schmidt, Piotr Grabarczyk, Lars R Jensen, Grzegorz K Przybylski, Matthias Port, Andreas W Kuss, Reinhard Ullmann
In classical models of tumorigenesis, the accumulation of tumor promoting chromosomal aberrations is described as a gradual process. Next-generation sequencing-based methods have recently revealed complex patterns of chromosomal aberrations, which are beyond explanation by these classical models of karyotypic evolution of tumor genomes. Thus, the term chromothripsis has been introduced to describe a phenomenon, where temporarily and spatially confined genomic instability results in dramatic chromosomal rearrangements limited to segments of one or a few chromosomes...
2018: Frontiers in Oncology
Atif J Khan, Sarah M Misenko, Aditya Thandoni, Devora Schiff, Sachin R Jhawar, Samuel F Bunting, Bruce G Haffty
Purpose: DNA double-strand breaks (DSBs) can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). We demonstrate the selectivity of VX-984, a DNA-PK inhibitor, using assays not previously reported. Experimental Design: The class switch recombination assay (CSR) in primary B cells was used to measure efficiency of NHEJ. A cellular reporter assay (U2OS EJ-DR) was used to assess the efficiency of HR and NHEJ in cells treated with VX-984...
May 25, 2018: Oncotarget
Max Gerlach, Theresia Kraft, Bernhard Brenner, Björn Petersen, Heiner Niemann, Judith Montag
During CRISPR/Cas9 mediated genome editing, site-specific double strand breaks are introduced and repaired either unspecific by non-homologous end joining (NHEJ) or sequence dependent by homology directed repair (HDR). Whereas NHEJ-based generation of gene knock-out is widely performed, the HDR-based knock-in of specific mutations remains a bottleneck. Especially in primary cell lines that are essential for the generation of cell culture and animal models of inherited human diseases, knock-in efficacy is insufficient and needs significant improvement...
June 13, 2018: Genes
Claudia Winkler, Raphael Rouget, Dan Wu, Monique Beullens, Aleyde Van Eynde, Mathieu Bollen
The ubiquitously expressed nuclear protein NIPP1 recruits phosphoproteins for regulated dephosphorylation by associated protein phosphatase PP1. To bypass PP1 titration artifacts of NIPP1 overexpression we have engineered covalently linked fusions of PP1 and NIPP1, and demonstrate their potential to selectively explore the function of the PP1:NIPP1 holoenzyme. Using inducible stable cell lines we show that PP1-NIPP1 fusions cause replication stress in a manner that requires both PP1 activity and substrate recruitment via the ForkHead Associated domain of NIPP1...
June 13, 2018: Journal of Cell Science
Bénédicte Michel, Anurag K Sinha, David R F Leach
In all organisms, replication impairments are an important source of genome rearrangements, mainly because of the formation of double-stranded DNA (dsDNA) ends at inactivated replication forks. Three reactions for the formation of dsDNA ends at replication forks were originally described for Escherichia coli and became seminal models for all organisms: the encounter of replication forks with preexisting single-stranded DNA (ssDNA) interruptions, replication fork reversal, and head-to-tail collisions of successive replication rounds...
September 2018: Microbiology and Molecular Biology Reviews: MMBR
Susan T Lovett
Amarh et al. (2018. J. Cell Biol. visualize for the first time the repair of double-strand breaks during DNA replication. As viewed by live-cell fluorescent imaging of Escherichia coli , repair of replication-dependent breaks is extraordinarily rapid and localized within the cell.
June 12, 2018: Journal of Cell Biology
Chengxian Ma, Kyungsoo Ha, Min-Su Kim, Young-Woock Noh, Han Lin, Lichun Tang, Qing Zhu, Dan Zhang, Huan Chen, Suxia Han, Pumin Zhang
Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). The choice between these two pathways is largely influenced by cell cycle phases. HDR can occur only in S/G2 when sister chromatid can provide homologous templates, whereas NHEJ can take place in all phases of the cell cycle except mitosis. Central to NHEJ repair is the Ku70/80 heterodimer which forms a ring structure that binds DSB ends and serves as a platform to recruit factors involved in NHEJ...
June 12, 2018: Cell Cycle
Dmitri Sisario, Simon Memmel, Sören Doose, Julia Neubauer, Heiko Zimmermann, Michael Flentje, Cholpon S Djuzenova, Markus Sauer, Vladimir L Sukhorukov
Induction of DNA double-strand breaks (DSBs) by ionizing radiation leads to formation of micrometer-sized DNA-repair foci, whose organization on the nanometer-scale remains unknown because of the diffraction limit (∼200 nm) of conventional microscopy. Here, we applied diffraction-unlimited, direct stochastic optical-reconstruction microscopy ( dSTORM) with a lateral resolution of ∼20 nm to analyze the focal nanostructure of the DSB marker histone γH2AX and the DNA-repair protein kinase (DNA-PK) in irradiated glioblastoma multiforme cells...
June 12, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Nasrin Yazdanpanahi, Rasoul Salehi, Sara Kamali
Background and Aim of Study: Colorectal cancer (CRC) is among the most common cancers and accounts as the second leading cause of death from cancers in the world. RAD51 plays a crucial role in double-strand breaks repair of DNA. Single nucleotide polymorphisms within this gene could influence on the potential of DNA repair and in consequence on the susceptibility to various tumors such as CRC. This is the first report about the role of RAD51 polymorphisms in Iranian CRC susceptibility...
April 2018: Journal of Cancer Research and Therapeutics
Guillaume Vogin, Thierry Bastogne, Larry Bodgi, Julien Gillet-Daubin, Aurélien Canet, Sandrine Pereira, Nicolas Foray
PURPOSE: The ability to identify, before treatment, those patients who will overreact to radiation therapy would have sound positive clinical implications. By focusing on DNA double-strand breaks recognition and repair proteins after irradiation, we recently demonstrated that the maximal number of phosphorylated ATM (pATM) nuclear foci in the first hour (pATMmax) after ex vivo irradiation correlated with postradiation therapy toxicity severity. We performed additional analyses of our whole collection of fibroblast lines to refine the predictive performance of our assay...
July 1, 2018: International Journal of Radiation Oncology, Biology, Physics
Robert J Ihry, Kathleen A Worringer, Max R Salick, Elizabeth Frias, Daniel Ho, Kraig Theriault, Sravya Kommineni, Julie Chen, Marie Sondey, Chaoyang Ye, Ranjit Randhawa, Tripti Kulkarni, Zinger Yang, Gregory McAllister, Carsten Russ, John Reece-Hoyes, William Forrester, Gregory R Hoffman, Ricardo Dolmetsch, Ajamete Kaykas
CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells1-3 . Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells3-13 . Here, using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), we achieved an average insertion or deletion (indel) efficiency greater than 80%...
June 11, 2018: Nature Medicine
Keiko Kawauchi, Wataru Sugimoto, Takatoshi Yasui, Kohei Murata, Katsuhiko Itoh, Kazuki Takagi, Takaaki Tsuruoka, Kensuke Akamatsu, Hisae Tateishi-Karimata, Naoki Sugimoto, Daisuke Miyoshi
Aberrant activation of RAS signalling pathways contributes to aggressive phenotypes of cancer cells. The RAS-targeted therapies for cancer, therefore, have been recognised to be effective; however, current developments on targeting RAS have not advanced due to structural features of the RAS protein. Here, we show that expression of NRAS, a major isoform of RAS, can be controlled by photo-irradiation with an anionic phthalocyanine, ZnAPC, targeting NRAS mRNA. In vitro experiments reveal that ZnAPC binds to a G-quadruplex-forming oligonucleotide derived from the 5'-untranslated region of NRAS mRNA even in the presence of excess double-stranded RNA, which is abundant in cells, resulting in selective cleavage of the target RNA's G-quadruplex upon photo-irradiation...
June 11, 2018: Nature Communications
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