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Replication fork

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https://www.readbyqxmd.com/read/27918542/the-role-of-break-induced-replication-in-large-scale-expansions-of-cag-n-ctg-n-repeats
#1
Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah, Sergei M Mirkin
Expansions of (CAG)n/(CTG)n trinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are commonly observed in human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism may lead to a large-scale repeat expansion as a single step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n/(CTG)n repeats in Saccharomyces cerevisiae...
December 5, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27915243/signaling-pathways-of-replication-stress-in-yeast
#2
Benjamin Pardo, Laure Crabbé, Philippe Pasero
Eukaryotic cells activate the S-phase checkpoint in response to a variety of events affecting the progression of replication forks, collectively referred to as replication stress. This signaling pathway is divided in two branches: the DNA damage checkpoint (DDC) and the DNA replication checkpoint (DRC). Both pathways are activated by the sensor kinase Mec1 and converge on the effector kinase Rad53. However, the DDC operates throughout the cell cycle and depends on the checkpoint mediator Rad9 to activate Rad53, whereas the DRC is specific to S phase and is mediated by Mrc1 and other fork components to signal replication impediments...
December 2, 2016: FEMS Yeast Research
https://www.readbyqxmd.com/read/27915231/predominant-role-of-dna-polymerase-eta-and-p53-dependent-translesion-synthesis-in-the-survival-of-ultraviolet-irradiated-human-cells
#3
Leticia K Lerner, Guilherme Francisco, Daniela T Soltys, Clarissa R R Rocha, Annabel Quinet, Alexandre T Vessoni, Ligia P Castro, Taynah I P David, Silvina O Bustos, Bryan E Strauss, Vanesa Gottifredi, Anne Stary, Alain Sarasin, Roger Chammas, Carlos F M Menck
Genome lesions trigger biological responses that help cells manage damaged DNA, improving cell survival. Pol eta is a translesion synthesis (TLS) polymerase that bypasses lesions that block replicative polymerases, avoiding continued stalling of replication forks, which could lead to cell death. p53 also plays an important role in preventing cell death after ultraviolet (UV) light exposure. Intriguingly, we show that p53 does so by favoring translesion DNA synthesis by pol eta. In fact, the p53-dependent induction of pol eta in normal and DNA repair-deficient XP-C human cells after UV exposure has a protective effect on cell survival after challenging UV exposures, which was absent in p53- and Pol H-silenced cells...
December 2, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27914716/replication-stalling-and-dna-microsatellite-instability
#4
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/27913728/fission-yeast-stn1-is-crucial-for-semi-conservative-replication-at-telomeres-and-subtelomeres
#5
Masahiro Takikawa, Yusuke Tarumoto, Fuyuki Ishikawa
The CST complex is a phylogenetically conserved protein complex consisting of CTC1/Cdc13, Stn1 and Ten1 that protects telomeres on linear chromosomes. Deletion of the fission yeast homologs stn1 and ten1 results in complete telomere loss; however, the precise function of Stn1 is still largely unknown. Here, we have isolated a high-temperature sensitive stn1 allele (termed stn1-1). stn1-1 cells abruptly lost telomeric sequence almost completely at the restrictive temperature. The loss of chromosomal DNA happened without gradual telomere shortening, and extended to 30 kb from the ends of chromosomes...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27912056/conflict-resolution-in-the-genome-how-transcription-and-replication-make-it-work
#6
REVIEW
Stephan Hamperl, Karlene A Cimprich
The complex machineries involved in replication and transcription translocate along the same DNA template, often in opposing directions and at different rates. These processes routinely interfere with each other in prokaryotes, and mounting evidence now suggests that RNA polymerase complexes also encounter replication forks in higher eukaryotes. Indeed, cells rely on numerous mechanisms to avoid, tolerate, and resolve such transcription-replication conflicts, and the absence of these mechanisms can lead to catastrophic effects on genome stability and cell viability...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27911848/global-analysis-of-genomic-instability-caused-by-dna-replication-stress-in-saccharomyces-cerevisiae
#7
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/27902925/targeted-inhibition-of-wrn-helicase-replication-stress-and-cancer
#8
REVIEW
Natalie Orlovetskie, Raphael Serruya, Ghada Abboud-Jarrous, Nayef Jarrous
WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest...
November 27, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27898391/replication-fork-instability-and-the-consequences-of-fork-collisions-from-rereplication
#9
REVIEW
Jessica L Alexander, Terry L Orr-Weaver
Replication forks encounter obstacles that must be repaired or bypassed to complete chromosome duplication before cell division. Proteomic analysis of replication forks suggests that the checkpoint and repair machinery travels with unperturbed forks, implying that they are poised to respond to stalling and collapse. However, impaired fork progression still generates aberrations, including repeat copy number instability and chromosome rearrangements. Deregulated origin firing also causes fork instability if a newer fork collides with an older one, generating double-strand breaks (DSBs) and partially rereplicated DNA...
October 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27893298/replication-checkpoint-suppression-and-structure-of-centromeric-dna
#10
Francesco Romeo, Lucia Falbo, Vincenzo Costanzo
Human centromeres contain large amounts of repetitive DNA sequences known as α satellite DNA, which can be difficult to replicate and whose functional role is unclear. Recently, we have characterized protein composition, structural organization and checkpoint response to stalled replication forks of centromeric chromatin reconstituted in Xenopus laevis egg extract. We showed that centromeric DNA has high affinity for SMC2-4 subunits of condensins and for CENP-A, it is enriched for DNA repair factors and suppresses the ATR checkpoint to ensure its efficient replication...
November 28, 2016: Nucleus
https://www.readbyqxmd.com/read/27892797/nek8-regulates-dna-damage-induced-rad51-foci-formation-and-replication-fork-protection
#11
Antonio Abeyta, Maria Castella, Celine Jacquemont, Toshiyasu Taniguchi
Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout...
November 28, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27889453/simultaneous-real-time-imaging-of-leading-and-lagging-strand-synthesis-reveals-the-coordination-dynamics-of-single-replisomes
#12
Karl E Duderstadt, Hylkje J Geertsema, Sarah A Stratmann, Christiaan M Punter, Arkadiusz W Kulczyk, Charles C Richardson, Antoine M van Oijen
The molecular machinery responsible for DNA replication, the replisome, must efficiently coordinate DNA unwinding with priming and synthesis to complete duplication of both strands. Due to the anti-parallel nature of DNA, the leading strand is copied continuously, while the lagging strand is produced by repeated cycles of priming, DNA looping, and Okazaki-fragment synthesis. Here, we report a multidimensional single-molecule approach to visualize this coordination in the bacteriophage T7 replisome by simultaneously monitoring the kinetics of loop growth and leading-strand synthesis...
November 15, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27889450/rpa-mediates-recruitment-of-mrx-to-forks-and-double-strand-breaks-to-hold-sister-chromatids-together
#13
Andrew Seeber, Anna Maria Hegnauer, Nicole Hustedt, Ishan Deshpande, Jérôme Poli, Jan Eglinger, Philippe Pasero, Heinz Gut, Miki Shinohara, Karl-Peter Hopfner, Kenji Shimada, Susan M Gasser
The Mre11-Rad50-Xrs2 (MRX) complex is related to SMC complexes that form rings capable of holding two distinct DNA strands together. MRX functions at stalled replication forks and double-strand breaks (DSBs). A mutation in the N-terminal OB fold of the 70 kDa subunit of yeast replication protein A, rfa1-t11, abrogates MRX recruitment to both types of DNA damage. The rfa1 mutation is functionally epistatic with loss of any of the MRX subunits for survival of replication fork stress or DSB recovery, although it does not compromise end-resection...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27876548/the-effects-of-replication-stress-on-s-phase-histone-management-and-epigenetic-memory
#14
REVIEW
Saša Šviković, Julian E Sale
When a cell divides it must not only accurately duplicate its genome but must also recapitulate its programme of gene expression. A significant body of evidence suggests that an important fraction of the information specifying the transcriptional programme of vertebrate cells is carried epigenetically by post-translational modifications of histone proteins. For such a system to operate, propagation of key histone marks must be coupled to replication such that they remain correctly associated with the underlying DNA sequence, despite the huge disruption to chromatin structure generated by unwinding the parental DNA strands...
November 19, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27876204/distinct-functions-of-human-recq-helicases-during-dna-replication
#15
Vaclav Urban, Jana Dobrovolna, Pavel Janscak
DNA replication is the most vulnerable process of DNA metabolism in proliferating cells and therefore it is tightly controlled and coordinated with processes that maintain genomic stability. Human RecQ helicases are among the most important factors involved in the maintenance of replication fork integrity, especially under conditions of replication stress. RecQ helicases promote recovery of replication forks being stalled due to different replication roadblocks of either exogenous or endogenous source. They prevent generation of aberrant replication fork structures and replication fork collapse, and are involved in proper checkpoint signaling...
November 15, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27871366/metalloprotease-sprtn-dvc1-orchestrates-replication-coupled-dna-protein-crosslink-repair
#16
Bruno Vaz, Marta Popovic, Joseph A Newman, John Fielden, Hazel Aitkenhead, Swagata Halder, Abhay Narayan Singh, Iolanda Vendrell, Roman Fischer, Ignacio Torrecilla, Neele Drobnitzky, Raimundo Freire, David J Amor, Paul J Lockhart, Benedikt M Kessler, Gillies W McKenna, Opher Gileadi, Kristijan Ramadan
The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity...
November 17, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27869662/the-cell-killing-mechanisms-of-hydroxyurea
#17
REVIEW
Amanpreet Singh, Yong-Jie Xu
Hydroxyurea is a well-established inhibitor of ribonucleotide reductase that has a long history of scientific interest and clinical use for the treatment of neoplastic and non-neoplastic diseases. It is currently the staple drug for the management of sickle cell anemia and chronic myeloproliferative disorders. Due to its reversible inhibitory effect on DNA replication in various organisms, hydroxyurea is also commonly used in laboratories for cell cycle synchronization or generating replication stress. However, incubation with high concentrations or prolonged treatment with low doses of hydroxyurea can result in cell death and the DNA damage generated at arrested replication forks is generally believed to be the direct cause...
November 17, 2016: Genes
https://www.readbyqxmd.com/read/27866901/histones-are-rapidly-loaded-onto-unintegrated-retroviral-dnas-soon-after-nuclear-entry
#18
Gary Z Wang, Ying Wang, Stephen P Goff
Chromosomal structure of nuclear DNA is usually maintained by insertion of nucleosomes into preexisting chromatin, both on newly synthesized DNA at replication forks and at sites of DNA damage. But during retrovirus infection, a histone-free DNA copy of the viral genome is synthesized that must be loaded with nucleosomes de novo. Here, we show that core histones are rapidly loaded onto unintegrated Moloney murine leukemia virus DNAs. Loading of nucleosomes requires nuclear entry, but does not require viral DNA integration...
November 9, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27863419/tsc-loss-distorts-dna-replication-programme-and-sensitises-cells-to-genotoxic-stress
#19
Govind M Pai, Alexandra Zielinski, Dennis Koalick, Kristin Ludwig, Zhao-Qi Wang, Kerstin Borgmann, Helmut Pospiech, Ignacio Rubio
Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27857978/wrnip1-a-new-guardian-of-genome-integrity-at-stalled-replication-forks
#20
Giuseppe Leuzzi, Veronica Marabitti, Pietro Pichierri, Annapaola Franchitto
Failure to protect and/or restart stalled replication forks contributes to genomic instability. Radiation-sensitive 51 (RAD51) recombinase defends stalled forks from nucleolytic attack, which otherwise can threaten their integrity. Recently, we have uncovered a novel and key function of Werner helicase interacting protein 1 (WRNIP1) as a fork-protective factor working in conjunction with RAD51 in response to replication stress.
2016: Molecular & Cellular Oncology
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