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Holliday junction

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https://www.readbyqxmd.com/read/28400564/a-novel-4-arm-dna-rna-nanoconstruct-triggering-rapid-apoptosis-of-triple-negative-breast-cancer-cells-within-24%C3%A2-hours
#1
Joline Tung, Lih Shin Tew, Yuan-Man Hsu, Yit Lung Khung
Measuring at ~30 nm, a fully customizable holliday junction DNA nanoconstruct, was designed to simultaneously carry three unmodified SiRNA strands for apoptosis gene knockout in cancer cells without any assistance from commercial transfection kits. In brief, a holliday junction structure was intelligently designed to present one arm with a cell targeting aptamer (AS1411) while the remaining three arms to carry different SiRNA strands by means of DNA/RNA duplex for inducing apoptosis in cancer cells. By carrying the three SiRNA strands (AKT, MDM2 and Survivin) into triple negative breast MDA-MB-231 cancer cells, cell number had reduced by up to ~82% within 24 hours solely from one single administration of 32 picomoles...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28393832/structural-insights-into-pot1-tpp1-interaction-and-pot1-c-terminal-mutations-in-human-cancer
#2
Cong Chen, Peili Gu, Jian Wu, Xianyun Chen, Shuangshuang Niu, Hong Sun, Lijie Wu, Na Li, Junhui Peng, Shaohua Shi, Cuiying Fan, Min Huang, Catherine C L Wong, Qingguo Gong, Chandan Kumar-Sinha, Rongguang Zhang, Lajos Pusztai, Rekha Rai, Sandy Chang, Ming Lei
Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPα-β complex, POT1-TPP1 adopts an elongated V-shaped conformation...
April 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28386965/perioperative-chemotherapy-versus-postoperative-chemoradiotherapy-in-patients-with-resectable-gastric-gastroesophageal-junction-adenocarcinomas-a-survival-analysis-of-5058-patients
#3
Timothy L Fitzgerald, Jimmy T Efird, Nelly Bellamy, Suzanne M Russo, Charulata Jindal, Catalina Mosquera, Elizabeth G Holliday, Tithi Biswas
BACKGROUND: Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas...
April 6, 2017: Cancer
https://www.readbyqxmd.com/read/28369583/substrate-preference-of-gen-endonucleases-highlights-the-importance-of-branched-structures-as-dna-damage-repair-intermediates
#4
Stephanie P Bellendir, Danielle J Rognstad, Lydia P Morris, Grzegorz Zapotoczny, William G Walton, Matthew R Redinbo, Dale A Ramsden, Jeff Sekelsky, Dorothy A Erie
Human GEN1 and yeast Yen1 are endonucleases with the ability to cleave Holliday junctions (HJs), which are proposed intermediates in recombination. In vivo, GEN1 and Yen1 function secondarily to Mus81, which has weak activity on intact HJs. We show that the genetic relationship is reversed in Drosophila, with Gen mutants having more severe defects than mus81 mutants. In vitro, DmGen, like HsGEN1, efficiently cleaves HJs, 5΄ flaps, splayed arms, and replication fork structures. We find that the cleavage rates for 5΄ flaps are significantly higher than those for HJs for both DmGen and HsGEN1, even in vast excess of enzyme over substrate...
March 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28357386/a-new-role-for-holliday-junction-resolvase-yen1-in-processing-dna-replication-intermediates-exposes-dna2-as-an-accessory-replicative-helicase
#5
COMMENT
Benoît Falquet, Ulrich Rass
DNA replication is mediated by a multi-protein complex known as the replisome. With the hexameric MCM (minichromosome maintenance) replicative helicase at its core, the replisome splits the parental DNA strands, forming replication forks (RFs), where it catalyses coupled leading and lagging strand DNA synthesis. While replication is a highly effective process, intrinsic and oncogene-induced replication stress impedes the progression of replisomes along chromosomes. As a consequence, RFs stall, arrest, and collapse, jeopardizing genome stability...
January 2, 2017: Microbial Cell
https://www.readbyqxmd.com/read/28356341/essential-role-for-centromeric-factors-following-p53-loss-and-oncogenic-transformation
#6
Dan Filipescu, Monica Naughtin, Katrina Podsypanina, Vincent Lejour, Laurence Wilson, Zachary A Gurard-Levin, Guillermo A Orsi, Iva Simeonova, Eleonore Toufektchan, Laura D Attardi, Franck Toledo, Geneviève Almouzni
In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A...
March 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28327556/control-of-structure-specific-endonucleases-to-maintain-genome-stability
#7
REVIEW
Pierre-Marie Dehé, Pierre-Henri L Gaillard
Structure-specific endonucleases (SSEs) have key roles in DNA replication, recombination and repair, and emerging roles in transcription. These enzymes have specificity for DNA secondary structure rather than for sequence, and therefore their activity must be precisely controlled to ensure genome stability. In this Review, we discuss how SSEs are controlled as part of genome maintenance pathways in eukaryotes, with an emphasis on the elaborate mechanisms that regulate the members of the major SSE families - including the xeroderma pigmentosum group F-complementing protein (XPF) and MMS and UV-sensitive protein 81 (MUS81)-dependent nucleases, and the flap endonuclease 1 (FEN1), XPG and XPG-like endonuclease 1 (GEN1) enzymes - during processes such as DNA adduct repair, Holliday junction processing and replication stress...
May 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28290553/slx4-prevents-gen1-dependent-dsbs-during-dna-replication-arrest-under-pathological-conditions-in-human-cells
#8
Eva Malacaria, Annapaola Franchitto, Pietro Pichierri
SLX4 is a versatile protein serving as docking for multiple structure-specific endonucleases during DNA repair, however, little is known about its function at demised replication forks. Using RNAi or FA-P cells complemented with SLX4 mutants that abrogate interaction with MUS81 or SLX1, we show that SLX4 cooperates with MUS81 to introduce DSBs after replication stress but also counteracts pathological targeting of demised forks by GEN1. Such unexpected function of SLX4 is unrelated to interaction with endonucleases, but concerns the physical presence of the protein...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28257701/the-smx-dna-repair-tri-nuclease
#9
Haley D M Wyatt, Rob C Laister, Stephen R Martin, Cheryl H Arrowsmith, Stephen C West
The efficient removal of replication and recombination intermediates is essential for the maintenance of genome stability. Resolution of these potentially toxic structures requires the MUS81-EME1 endonuclease, which is activated at prometaphase by formation of the SMX tri-nuclease containing three DNA repair structure-selective endonucleases: SLX1-SLX4, MUS81-EME1, and XPF-ERCC1. Here we show that SMX tri-nuclease is more active than the three individual nucleases, efficiently cleaving replication forks and recombination intermediates...
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28242723/resolution-of-mismatched-overlap-holliday-junction-intermediates-by-the-tyrosine-recombinase-intdot
#10
Kenneth Ringwald, Sumiko Yoneji, Jeffrey Gardner
CTnDOT is an integrated conjugative element found in Bacteroides species. CTnDOT encodes for and transfers antibiotic resistance genes. The element integrates into and excises from the host chromosome via a Holliday junction intermediate as part of a site-specific recombination mechanism. The CTnDOT integrase, IntDOT, is a tyrosine recombinase with core-binding, catalytic and amino terminal domains. Unlike well-studied tyrosine recombinases such as lambda Int, IntDOT is able to resolve Holliday junctions containing heterology (mismatched bases) between the sites of strand exchange...
February 27, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28238763/structure-and-function-of-a-novel-atpase-that-interacts-with-holliday-junction-resolvase-hjc-and-promotes-branch-migration
#11
Binyuan Zhai, Kevin DuPrez, Tzanko I Doukov, Huan Li, Mengting Huang, Guijun Shang, Jinfeng Ni, Lichuan Gu, Yulong Shen, Li Fan
Holliday junction (HJ) is a hallmark intermediate in DNA recombination and must be processed by dissolution (for double HJ) or resolution to ensure genome stability. Although HJ resolvases have been identified in all domains of life, there is a long-standing effort to search in prokaryotes and eukarya for proteins promoting HJ migration. Here, we report the structural and functional characterization of a novel ATPase, Sulfolobus islandicusPilT N-terminal-domain-containing ATPase (SisPINA), encoded by the gene adjacent to the resolvase Hjc coding gene...
February 24, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28179392/human-cell-assays-for-synthesis-dependent-strand-annealing-and-crossing-over-during-double-strand-break-repair
#12
Grzegorz Zapotoczny, Jeff Sekelsky
DNA double-strand breaks (DSBs) are one of the most deleterious types of lesions to the genome. Synthesis-dependent strand annealing (SDSA) is thought to be a major pathway of DSB repair, but direct tests of this model have only been conducted in budding yeast and Drosophila To better understand this pathway, we developed an SDSA assay for use in human cells. Our results support the hypothesis that SDSA is an important DSB repair mechanism in human cells. We used siRNA knockdown to assess the roles of a number of helicases suggested to promote SDSA...
April 3, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28090586/holliday-junction-trap-shows-how-cells-use-recombination-and-a-junction-guardian-role-of-recq-helicase
#13
Jun Xia, Li-Tzu Chen, Qian Mei, Chien-Hui Ma, Jennifer A Halliday, Hsin-Yu Lin, David Magnan, John P Pribis, Devon M Fitzgerald, Holly M Hamilton, Megan Richters, Ralf B Nehring, Xi Shen, Lei Li, David Bates, P J Hastings, Christophe Herman, Makkuni Jayaram, Susan M Rosenberg
DNA repair by homologous recombination (HR) underpins cell survival and fuels genome instability, cancer, and evolution. However, the main kinds and sources of DNA damage repaired by HR in somatic cells and the roles of important HR proteins remain elusive. We present engineered proteins that trap, map, and quantify Holliday junctions (HJs), a central DNA intermediate in HR, based on catalytically deficient mutant RuvC protein of Escherichia coli. We use RuvCDefGFP (RDG) to map genomic footprints of HR at defined DNA breaks in E...
November 2016: Science Advances
https://www.readbyqxmd.com/read/28051169/intercalative-dna-binding-of-the-marine-anticancer-drug-variolin-b
#14
Albert Canals, Raquel Arribas-Bosacoma, Fernando Albericio, Mercedes Álvarez, Joan Aymamí, Miquel Coll
Variolin B is a rare marine alkaloid that showed promising anti-cancer activity soon after its isolation. It acts as a cyclin-dependent kinase inhibitor, although the precise mechanism through which it exerts the cytotoxic effects is still unknown. The crystal structure of a variolin B bound to a DNA forming a pseudo-Holliday junction shows that this compound can also contribute, through intercalative binding, to either the formation or stabilization of multi-stranded DNA forms.
January 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28049850/resolution-of-single-and-double-holliday-junction-recombination-intermediates-by-gen1
#15
Rajvee Shah Punatar, Maria Jose Martin, Haley D M Wyatt, Ying Wai Chan, Stephen C West
Genetic recombination provides an important mechanism for the repair of DNA double-strand breaks. Homologous pairing and strand exchange lead to the formation of DNA intermediates, in which sister chromatids or homologous chromosomes are covalently linked by four-way Holliday junctions (HJs). Depending on the type of recombination reaction that takes place, intermediates may have single or double HJs, and their resolution is essential for proper chromosome segregation. In mitotic cells, double HJs are primarily dissolved by the BLM helicase-TopoisomeraseIIIα-RMI1-RMI2 (BTR) complex, whereas single HJs (and double HJs that have escaped the attention of BTR) are resolved by structure-selective endonucleases known as HJ resolvases...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28049740/resolvase-osgen1-mediates-dna-repair-by-homologous-recombination
#16
Chong Wang, James D Higgins, Yi He, Pingli Lu, Dabing Zhang, Wanqi Liang
Yen1/GEN1 are canonical Holliday junction resolvases that belong to the RAD2/XPG family. In eukaryotes, such as budding yeast, mice, worms, and humans, Yen1/GEN1 work together with Mus81-Mms4/MUS81-EME1 and Slx1-Slx4/SLX1-SLX4 in DNA repair by homologous recombination to maintain genome stability. In plants, the biological function of Yen1/GEN1 remains largely unclear. In this study, we characterized the loss of function mutants of OsGEN1 and OsSEND1, a pair of paralogs of Yen1/GEN1 in rice (Oryza sativa). We first investigated the role of OsGEN1 during meiosis and found a reduction in chiasma frequency by ∼6% in osgen1 mutants, compared to the wild type, suggesting a possible involvement of OsGEN1 in the formation of crossovers...
February 2017: Plant Physiology
https://www.readbyqxmd.com/read/27990631/holliday-junction-resolving-enzymes-structures-and-mechanisms
#17
REVIEW
David M J Lilley
Holliday junction-resolving enzymes are nucleases that are highly specific for the structure of the junction, to which they bind in dimeric form. Two symmetrically disposed cleavages are made. These are not simultaneous, but the second cleavage is accelerated relative to the first, so ensuring that bilateral cleavage occurs during the lifetime of the DNA-protein complex. In eukaryotic cells there are two known junction-resolving activities. GEN1 is similar to enzymes from lower organisms. A crystallographic structure of a fungal GEN1 bound to the product of resolution has been determined...
April 2017: FEBS Letters
https://www.readbyqxmd.com/read/27977684/loss-of-rmi2-increases-genome-instability-and-causes-a-bloom-like-syndrome
#18
Damien F Hudson, David J Amor, Amber Boys, Kathy Butler, Lorna Williams, Tao Zhang, Paul Kalitsis
Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27977207/photon-by-photon-hidden-markov-model-analysis-for-microsecond-single-molecule-fret-kinetics
#19
Menahem Pirchi, Roman Tsukanov, Rashid Khamis, Toma E Tomov, Yaron Berger, Dinesh C Khara, Hadas Volkov, Gilad Haran, Eyal Nir
The function of biological macromolecules involves large-scale conformational dynamics spanning multiple time scales, from microseconds to seconds. Such conformational motions, which may involve whole domains or subunits of a protein, play a key role in allosteric regulation. There is an urgent need for experimental methods to probe the fastest of these motions. Single-molecule fluorescence experiments can in principle be used for observing such dynamics, but there is a lack of analysis methods that can extract the maximum amount of information from the data, down to the microsecond time scale...
December 29, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27923713/when-transcription-goes-on-holliday-double-holliday-junctions-block-rna-polymerase-ii-transcription-in-vitro
#20
Anne Pipathsouk, Boris P Belotserkovskii, Philip C Hanawalt
Non-canonical DNA structures can obstruct transcription. This transcription blockage could have various biological consequences, including genomic instability and gratuitous transcription-coupled repair. Among potential structures causing transcription blockage are Holliday junctions (HJs), which can be generated as intermediates in homologous recombination or during processing of stalled replication forks. Of particular interest is the double Holliday junction (DHJ), which contains two HJs. Topological considerations impose the constraint that the total number of helical turns in the DNA duplexes between the junctions cannot be altered as long as the flanking DNA duplexes are intact...
February 2017: Biochimica et Biophysica Acta
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