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https://www.readbyqxmd.com/read/28934496/activities-of-gyrase-and-topoisomerase-iv-on-positively-supercoiled-dna
#1
Rachel E Ashley, Andrew Dittmore, Sylvia A McPherson, Charles L Turnbough, Keir C Neuman, Neil Osheroff
Although bacterial gyrase and topoisomerase IV have critical interactions with positively supercoiled DNA, little is known about the actions of these enzymes on overwound substrates. Therefore, the abilities of Bacillus anthracis and Escherichia coli gyrase and topoisomerase IV to relax and cleave positively supercoiled DNA were analyzed. Gyrase removed positive supercoils ∼10-fold more rapidly and more processively than it introduced negative supercoils into relaxed DNA. In time-resolved single-molecule measurements, gyrase relaxed overwound DNA with burst rates of ∼100 supercoils per second (average burst size was 6...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28924044/nuclear-insulin-like-growth-factor-1-receptor-phosphorylates-proliferating-cell-nuclear-antigen-and-rescues-stalled-replication-forks-after-dna-damage
#2
Ahmed Waraky, Yingbo Lin, Dudi Warsito, Felix Haglund, Eiman Aleem, Olle Larsson
We have previously shown that the insulin like growth factor 1 receptor (IGF1R) translocates to the cell nucleus, where it binds to enhancer like regions and increases gene transcription. Further studies have demonstrated that nuclear IGF1R (nIGF1R) physically and functionally interacts with some nuclear proteins, i.e. the lymphoid enhancer binding factor 1 (Lef1), histone H3, and Brahma related gene 1 proteins. In the present study, we identified the proliferating cell nuclear antigen (PCNA) as a nIGF1R binding partner...
September 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28923950/single-molecule-visualization-of-saccharomyces-cerevisiae-leading-strand-synthesis-reveals-dynamic-interaction-between-mtc-and-the-replisome
#3
Jacob S Lewis, Lisanne M Spenkelink, Grant D Schauer, Flynn R Hill, Roxanna E Georgescu, Michael E O'Donnell, Antoine M van Oijen
The replisome, the multiprotein system responsible for genome duplication, is a highly dynamic complex displaying a large number of different enzyme activities. Recently, the Saccharomyces cerevisiae minimal replication reaction has been successfully reconstituted in vitro. This provided an opportunity to uncover the enzymatic activities of many of the components in a eukaryotic system. Their dynamic behavior and interactions in the context of the replisome, however, remain unclear. We use a tethered-bead assay to provide real-time visualization of leading-strand synthesis by the S...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28922417/lingering-single-strand-breaks-trigger-rad51-independent-homology-directed-repair-of-collapsed-replication-forks-in-the-polynucleotide-kinase-phosphatase-mutant-of-fission-yeast
#4
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 18, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28921956/recognition-of-dna-supercoil-geometry-by-mycobacterium-tuberculosis-gyrase
#5
Rachel E Ashley, Tim R Blower, James M Berger, Neil Osheroff
Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M...
September 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28915668/nsc30049-inhibits-chk1-pathway-in-5-fu-resistant-crc-bulk-and-stem-cell-populations
#6
Satya Narayan, Aruna S Jaiswal, Ritika Sharma, Akbar Nawab, Lizette Vila Duckworth, Brian K Law, Maria Zajac-Kaye, Thomas J George, Jay Sharma, Arun K Sharma, Robert A Hromas
The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915237/dna-replication-stress-restricts-ribosomal-dna-copy-number
#7
Devika Salim, William D Bradford, Amy Freeland, Gillian Cady, Jianmin Wang, Steven C Pruitt, Jennifer L Gerton
Ribosomal RNAs (rRNAs) in budding yeast are encoded by ~100-200 repeats of a 9.1kb sequence arranged in tandem on chromosome XII, the ribosomal DNA (rDNA) locus. Copy number of rDNA repeat units in eukaryotic cells is maintained far in excess of the requirement for ribosome biogenesis. Despite the importance of the repeats for both ribosomal and non-ribosomal functions, it is currently not known how "normal" copy number is determined or maintained. To identify essential genes involved in the maintenance of rDNA copy number, we developed a droplet digital PCR based assay to measure rDNA copy number in yeast and used it to screen the yeast conditional temperature-sensitive mutant collection of essential genes...
September 15, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28904335/brca2-suppresses-replication-stress-induced-mitotic-and-g1-abnormalities-through-homologous-recombination
#8
Weiran Feng, Maria Jasin
Mutations in the tumor suppressor BRCA2 predominantly predispose to breast cancer. Paradoxically, while loss of BRCA2 promotes tumor formation, it also causes cell lethality, although how lethality is triggered is unclear. Here, we generate BRCA2 conditional non-transformed human mammary epithelial cell lines using CRISPR-Cas9. Cells are inviable upon BRCA2 loss, which leads to replication stress associated with under replication, causing mitotic abnormalities, 53BP1 nuclear body formation in the ensuing G1 phase, and G1 arrest...
September 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28900015/structure-and-function-of-pif1-helicase
#9
REVIEW
Alicia K Byrd, Kevin D Raney
Pif1 family helicases have multiple roles in the maintenance of nuclear and mitochondrial DNA in eukaryotes. Saccharomyces cerevisiae Pif1 is involved in replication through barriers to replication, such as G-quadruplexes and protein blocks, and reduces genetic instability at these sites. Another Pif1 family helicase in S. cerevisiae, Rrm3, assists in fork progression through replication fork barriers at the rDNA locus and tRNA genes. ScPif1 (Saccharomyces cerevisiae Pif1) also negatively regulates telomerase, facilitates Okazaki fragment processing, and acts with polymerase δ in break-induced repair...
September 12, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28898504/reversible-dna-protein-cross-linking-at-epigenetic-dna-marks
#10
Shaofei Ji, Hongzhao Shao, Qiyuan Han, Christopher L Seiler, Natalia Tretyakova
5-Formylcytosine (5fC) is an endogenous DNA modification frequently found within regulatory elements of mammalian genes. Although 5fC is an oxidation product of 5-methylcytosine (5mC), the two epigenetic marks show distinct genome-wide distributions and protein affinities, suggesting that they perform different functions in epigenetic signaling. A unique feature of 5fC is the presence of a potentially reactive aldehyde group in its structure. Here, we show that 5fC bases in DNA readily form Schiff base conjugates with Lys side chains of nuclear proteins in vitro and in vivo...
September 12, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28894029/pari-regulates-stalled-replication-fork-processing-to-maintain-genome-stability-upon-replication-stress-in-mice
#11
Ayako L Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai, Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, Shinichiro Chuma
DNA replication is frequently perturbed by intrinsic as well as extrinsic genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain the genome integrity. We show here that PARI anti-recombinase plays an essential role to modulate the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent strand shortening that is regulated by RAD51 and MRE11...
September 11, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28892026/purification-of-viral-dna-for-the-identification-of-associated-viral-and-cellular-proteins
#12
Jill A Dembowski, Neal A Deluca
The goal of this protocol is to isolate herpes simplex virus type 1 (HSV-1) DNA from infected cells for the identification of associated viral and cellular proteins by mass spectrometry. Although proteins that interact with viral genomes play major roles in determining the outcome of infection, a comprehensive analysis of viral genome associated proteins was not previously feasible. Here we demonstrate a method that enables the direct purification of HSV-1 genomes from infected cells. Replicating viral DNA is selectively labeled with modified nucleotides that contain an alkyne functional group...
August 31, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28890386/co-targeting-c-met-and-dna-double-strand-breaks-dsbs-therapeutic-strategies-in-brca-mutated-gastric-carcinomas
#13
REVIEW
Chrysovalantou Mihailidou, Michalis V Karamouzis, Dimitrios Schizas, Athanasios G Papavassiliou
Gastric cancer (GC) is a threatening malignancy characterized by heterogeneity. Current therapies use DNA damaging agents, for example, chemotherapeutic agents and ionizing radiation (IR). However, a significant portion of GC patients develops therapeutic resistance to DNA damage response (DDR) - inducing agents. An important mechanism is the stimulation of the c-MET RTK, which is a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), which facilitates cell survival by boosting DNA damage repair pathways and via escaping cell cycle arrest...
September 7, 2017: Biochimie
https://www.readbyqxmd.com/read/28888173/lc-ms-ms-assay-for-the-quantitation-of-the-atr-kinase-inhibitor-vx-970-in-human-plasma
#14
Brian F Kiesel, Jonas Scemama, Robert A Parise, Liza Villaruz, Andre Iffland, Austin Doyle, Percy Ivy, Edward Chu, Christopher J Bakkenist, Jan H Beumer
DNA damaging chemotherapy and radiation are widely used standard-of-care modalities for the treatment of cancer. Nevertheless, the outcome for many patients remains poor and this may be attributed, at least in part, to highly effective DNA repair mechanisms. Ataxia-telangiectasia mutated and Rad3-related (ATR) is a key regulator of the DNA-damage response (DDR) that orchestrates the repair of damaged replication forks. ATR is a serine/threonine protein kinase and ATR kinase inhibitors potentiate chemotherapy and radiation...
August 31, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28886337/replication-fork-slowing-and-reversal-upon-dna-damage-require-pcna-polyubiquitination-and-zranb3-dna-translocase-activity
#15
Marko Vujanovic, Jana Krietsch, Maria Chiara Raso, Nastassja Terraneo, Ralph Zellweger, Jonas A Schmid, Angelo Taglialatela, Jen-Wei Huang, Cory L Holland, Katharina Zwicky, Raquel Herrador, Heinz Jacobs, David Cortez, Alberto Ciccia, Lorenza Penengo, Massimo Lopes
DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28878163/recq1-helicase-silencing-decreases-the-tumour-growth-rate-of-u87-glioblastoma-cell-xenografts-in-zebrafish-embryos
#16
Miloš Vittori, Barbara Breznik, Katja Hrovat, Saša Kenig, Tamara T Lah
RECQ1 helicase has multiple roles in DNA replication, including restoration of the replication fork and DNA repair, and plays an important role in tumour progression. Its expression is highly elevated in glioblastoma as compared to healthy brain tissue. We studied the effects of small hairpin RNA (shRNA)-induced silencing of RECQ1 helicase on the increase in cell number and the invasion of U87 glioblastoma cells. RECQ1 silencing reduced the rate of increase in the number of U87 cells by 30%. This corresponded with a 40% reduction of the percentage of cells in the G2 phase of the cell cycle, and an accumulation of cells in the G1 phase...
September 6, 2017: Genes
https://www.readbyqxmd.com/read/28874453/dna-replication-control-during-drosophila-development-insights-into-the-onset-of-s-phase-replication-initiation-and-fork-progression
#17
Brian L Hua, Terry L Orr-Weaver
Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation. In addition, differential regulation of the DNA replication program during development can change gene copy number to influence cell size and gene expression. Drosophila melanogaster serves as a powerful organism to study the developmental control of DNA replication in various cell cycle contexts in a variety of differentiated cell and tissue types. Additionally, Drosophila has provided several developmentally regulated replication models to dissect the molecular mechanisms that underlie replication-based copy number changes in the genome, which include differential underreplication and gene amplification...
September 2017: Genetics
https://www.readbyqxmd.com/read/28869037/mcm10-promotes-rapid-isomerization-of-cmg-dna-for-replisome-bypass-of-lagging-strand-dna-blocks
#18
Lance D Langston, Ryan Mayle, Grant D Schauer, Olga Yurieva, Daniel Zhang, Nina Y Yao, Roxana E Georgescu, Mike E O'Donnell
Replicative helicases in all cell types are hexameric rings that unwind DNA by steric exclusion in which the helicase encircles the tracking strand only and excludes the other strand from the ring. This mode of translocation allows helicases to bypass blocks on the strand that is excluded from the central channel. Unlike other replicative helicases, eukaryotic CMG helicase partially encircles duplex DNA at a forked junction and is stopped by a block on the non-tracking (lagging) strand. This report demonstrates that Mcm10, an essential replication protein unique to eukaryotes, binds CMG and greatly stimulates its helicase activity in vitro...
September 4, 2017: ELife
https://www.readbyqxmd.com/read/28860160/abro1-maintains-genome-stability-and-limits-replication-stress-by-protecting-replication-fork-stability
#19
Shengfeng Xu, Xiao Wu, Ling Wu, Andy Castillo, Jianxin Liu, Erin Atkinson, Atanu Paul, Dan Su, Katharina Schlacher, Yoshihiro Komatsu, M James You, Bin Wang
Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chromosome instability, and Abro1-null mice are tumor-prone. We show that Abro1 protects stalled replication fork stability by inhibiting DNA2 nuclease/WRN helicase-mediated degradation of stalled forks...
July 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28855376/destabilization-of-the-replication-fork-protection-complex-disrupts-meiotic-chromosome-segregation
#20
Wilber Escorcia, Susan L Forsburg
The replication fork protection complex (FPC) coordinates multiple processes that are crucial for unimpeded passage of the replisome through various barriers and difficult-to-replicate areas of the genome. We examine the function of Swi1 and Swi3, fission yeast's primary FPC components, to elucidate how replication fork stability contributes to DNA integrity in meiosis. We report that destabilization of the FPC results in reduced spore viability, delayed replication, changes in recombination, and chromosome mis-segregation in MI and MII...
August 30, 2017: Molecular Biology of the Cell
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