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Replication fork

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https://www.readbyqxmd.com/read/28211448/cx-5461-is-a-dna-g-quadruplex-stabilizer-with-selective-lethality-in-brca1-2-deficient-tumours
#1
Hong Xu, Marco Di Antonio, Steven McKinney, Veena Mathew, Brandon Ho, Nigel J O'Neil, Nancy Dos Santos, Jennifer Silvester, Vivien Wei, Jessica Garcia, Farhia Kabeer, Daniel Lai, Priscilla Soriano, Judit Banáth, Derek S Chiu, Damian Yap, Daniel D Le, Frank B Ye, Anni Zhang, Kelsie Thu, John Soong, Shu-Chuan Lin, Angela Hsin Chin Tsai, Tomo Osako, Teresa Algara, Darren N Saunders, Jason Wong, Jian Xian, Marcel B Bally, James D Brenton, Grant W Brown, Sohrab P Shah, David Cescon, Tak W Mak, Carlos Caldas, Peter C Stirling, Phil Hieter, Shankar Balasubramanian, Samuel Aparicio
G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks...
February 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28208741/mechanisms-of-post-replication-dna-repair
#2
REVIEW
Yanzhe Gao, Elizabeth Mutter-Rottmayer, Anastasia Zlatanou, Cyrus Vaziri, Yang Yang
Accurate DNA replication is crucial for cell survival and the maintenance of genome stability. Cells have developed mechanisms to cope with the frequent genotoxic injuries that arise from both endogenous and environmental sources. Lesions encountered during DNA replication are often tolerated by post-replication repair mechanisms that prevent replication fork collapse and avert the formation of DNA double strand breaks. There are two predominant post-replication repair pathways, trans-lesion synthesis (TLS) and template switching (TS)...
February 8, 2017: Genes
https://www.readbyqxmd.com/read/28204881/genetic-evidence-for-functional-interaction-of-smc5-6-complex-and-top1-with-spatial-frequency-of-replication-origins-required-for-maintenance-of-chromosome-stability
#3
Ragini Rai, Shikha Laloraya
Replication of linear chromosomes is facilitated by firing of multiple replication origins that ensures timely duplication of the entire chromosome. The Smc5/6 complex is thought to play an important role in replication by its involvement in the restart of collapsed replication forks. Here, we present genetic evidence for functional interaction between replication origin distribution and two subunits of the Smc5/6 complex, Smc6 and Mms21, as well as Top1. An artificial chromosome that has a long arm having low origin density (5ori∆YAC) is relatively unstable compared to the YAC having normal origin distribution in wild-type cells, but is partially stabilized in smc6-56 and top1∆ mutants...
February 16, 2017: Current Genetics
https://www.readbyqxmd.com/read/28197541/way-out-way-in-how-the-relationship-between-wrn-and-cdk1-may-change-the-fate-of-collapsed-replication-forks
#4
Valentina Palermo, Sara Rinalducci, Massimo Sanchez, Francesca Grillini, Annapaola Franchitto, Pietro Pichierri
Replication-dependent double-strand breaks (DSBs) are the main source of genomic instability as their inaccurate repair stimulates chromosomal rearrangements. In a recent work, we uncover a novel regulatory circuit that involves the Werner's syndrome helicase and CDK1, and that is essential for repair pathway choice at replication-dependent DSBs.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28191891/mutations-in-donson-disrupt-replication-fork-stability-and-cause-microcephalic-dwarfism
#5
John J Reynolds, Louise S Bicknell, Paula Carroll, Martin R Higgs, Ranad Shaheen, Jennie E Murray, Dimitrios K Papadopoulos, Andrea Leitch, Olga Murina, Žygimantė Tarnauskaitė, Sarah R Wessel, Anastasia Zlatanou, Audrey Vernet, Alex von Kriegsheim, Rachel M A Mottram, Clare V Logan, Hannah Bye, Yun Li, Alexander Brean, Sateesh Maddirevula, Rachel C Challis, Kassiani Skouloudaki, Agaadir Almoisheer, Hessa S Alsaif, Ariella Amar, Natalie J Prescott, Michael B Bober, Angela Duker, Eissa Faqeih, Mohammed Zain Seidahmed, Saeed Al Tala, Abdulrahman Alswaid, Saleem Ahmed, Jumana Yousuf Al-Aama, Janine Altmüller, Mohammed Al Balwi, Angela F Brady, Luciana Chessa, Helen Cox, Rita Fischetto, Raoul Heller, Bertram D Henderson, Emma Hobson, Peter Nürnberg, E Ferda Percin, Angela Peron, Luigina Spaccini, Alan J Quigley, Seema Thakur, Carol A Wise, Grace Yoon, Maha Alnemer, Pavel Tomancak, Gökhan Yigit, A Malcolm R Taylor, Martin A M Reijns, Michael A Simpson, David Cortez, Fowzan S Alkuraya, Christopher G Mathew, Andrew P Jackson, Grant S Stewart
To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks...
February 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28188145/structural-studies-of-rfc-c-tf18-reveal-a-novel-chromatin-recruitment-role-for-dcc1
#6
Benjamin O Wade, Hon Wing Liu, Catarina P Samora, Frank Uhlmann, Martin R Singleton
Replication factor C complexes load and unload processivity clamps from DNA and are involved in multiple DNA replication and repair pathways. The RFC(C)(tf18) variant complex is required for activation of the intra-S-phase checkpoint at stalled replication forks and aids the establishment of sister chromatid cohesion. Unlike other RFC complexes, RFC(C)(tf18) contains two non-Rfc subunits, Dcc1 and Ctf8. Here, we present the crystal structure of the Dcc1-Ctf8 heterodimer bound to the C-terminus of Ctf18. We find that the C-terminus of Dcc1 contains three-winged helix domains, which bind to both ssDNA and dsDNA We further show that these domains are required for full recruitment of the complex to chromatin, and correct activation of the replication checkpoint...
February 10, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28186504/a-defective-dntp-pool-hinders-dna-replication-in-cell-cycle-reactivated-terminally-differentiated-muscle-cells
#7
Deborah Pajalunga, Elisa Franzolin, Martina Stevanoni, Sara Zribi, Nunzia Passaro, Aymone Gurtner, Samantha Donsante, Daniela Loffredo, Lidia Losanno, Vera Bianchi, Antonella Russo, Chiara Rampazzo, Marco Crescenzi
Terminally differentiated cells are defined by their inability to proliferate. When forced to re-enter the cell cycle, they generally cannot undergo long-term replication. Our previous work with myotubes has shown that these cells fail to proliferate because of their intrinsic inability to complete DNA replication. Moreover, we have reported pronounced modifications of deoxynucleotide metabolism during myogenesis. Here we investigate the causes of incomplete DNA duplication in cell cycle-reactivated myotubes (rMt)...
February 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28177605/replication-protein-a-prohibits-diffusion-of-the-pcna-sliding-clamp-along-single-stranded-dna
#8
Mark Hedglin, Stephen J Benkovic
The replicative polymerases cannot accommodate distortions to the native DNA sequence such as modifications (lesions) to the native template bases from exposure to reactive metabolites and environmental mutagens. Consequently, DNA synthesis on an afflicted template abruptly stops upon encountering these lesions but the replication fork progresses onward, exposing long stretches of the damaged template before eventually stalling. Such arrests may be overcome by translesion DNA synthesis where a specialized TLS polymerases binds to the resident PCNA and replicates the damaged DNA...
February 8, 2017: Biochemistry
https://www.readbyqxmd.com/read/28173629/enhanced-dependency-of-kras-mutant-colorectal-cancer-cells-on-rad51-dependent-homologous-recombination-repair-identified-from-genetic-interactions-in-saccharomyces-cerevisiae
#9
Murugan Kalimutho, Amanda L Bain, Bipasha Mukherjee, Purba Nag, Devathri M Nanayakkara, Sarah K Harten, Janelle L Harris, Goutham Narayanan Subramanian, Debottam Sinha, Senji Shirasawa, Sriganesh Srihari, Sandeep Burma, Kum Kum Khanna
Activating KRAS mutations drive colorectal cancer tumorigenesis and influence response to anti-EGFR targeted therapy. Despite recent advances in understanding Ras signaling biology and the revolution in therapies for melanoma using BRAF inhibitors, no targeted agents have been effective in KRAS mutant cancers, mainly due to activation of compensatory pathways. Here, by leveraging the largest synthetic lethal genetic interactome in yeast, we identify that KRAS-mutated colorectal cancer cells have augmented homologous recombination repair (HRR) signaling...
February 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28170194/human-adipose-derived-stem-cells-expanded-under-ambient-oxygen-concentration-accumulate-oxidative-dna-lesions-and-experience-procarcinogenic-dna-replication-stress
#10
Rémy Bétous, Marie-Laure Renoud, Claire Hoede, Ignacio Gonzalez, Natalie Jones, Michel Longy, Luc Sensebé, Christophe Cazaux, Jean-Sébastien Hoffmann
Adipose-derived stem cells (ADSCs) have led to growing interest in cell-based therapy because they can be easily harvested from an abundant tissue. ADSCs must be expanded in vitro before transplantation. This essential step causes concerns about the safety of adult stem cells in terms of potential transformation. Tumorigenesis is driven in its earliest step by DNA replication stress, which is characterized by the accumulation of stalled DNA replication forks and activation of the DNA damage response. Thus, to evaluate the safety of ADSCs during ex vivo expansion, we monitored DNA replication under atmospheric (21%) or physiologic (1%) oxygen concentration...
January 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28166228/rapid-turnover-of-dnaa-at-replication-origin-regions-contributes-to-initiation-control-of-dna-replication
#11
Katrin Schenk, Ana B Hervás, Thomas C Rösch, Marc Eisemann, Bernhard A Schmitt, Stephan Dahlke, Luise Kleine-Borgmann, Seán M Murray, Peter L Graumann
DnaA is a conserved key regulator of replication initiation in bacteria, and is homologous to ORC proteins in archaea and in eukaryotic cells. The ATPase binds to several high affinity binding sites at the origin region and upon an unknown molecular trigger, spreads to several adjacent sites, inducing the formation of a helical super structure leading to initiation of replication. Using FRAP analysis of a functional YFP-DnaA allele in Bacillus subtilis, we show that DnaA is bound to oriC with a half-time of 2...
February 6, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28159842/direct-visualization-of-rna-dna-primer-removal-from-okazaki-fragments-provides-support-for-flap-cleavage-and-exonucleolytic-pathways-in-eukaryotic-cells
#12
Bochao Liu, Jiazhi Hu, Jingna Wang, Daochun Kong
During DNA replication in eukaryotic cells, short single-stranded DNA segments known as Okazaki fragments are first synthesized on the lagging strand. The Okazaki fragments originate from ~35 nt long RNA-DNA primers. After Okazaki fragment synthesis, these primers must be removed to allow fragment joining into a continuous lagging strand. To date, the models of enzymatic machinery that removes the RNA-DNA primers has come almost exclusively from biochemical reconstitution studies and some genetic interaction assays, and there is little direct evidence to confirm these models...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28157503/forging-ahead-through-darkness-pcna-still-the-principal-conductor-at-the-replication-fork
#13
REVIEW
Katherine N Choe, George-Lucian Moldovan
Proliferating cell nuclear antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it...
February 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28155219/recg-controls-dna-amplification-at-double-strand-breaks-and-arrested-replication-forks
#14
REVIEW
Benura Azeroglu, David Leach
DNA amplification is a powerful mutational mechanism that is a hallmark of cancer and drug resistance. It is therefore important to understand the fundamental pathways that cells employ to avoid over-replicating sections of their genomes. Recent studies demonstrate that, in the absence of RecG, DNA amplification is observed at sites of DNA double-strand break repair (DSBR) and of DNA replication arrest that are processed to generate double-strand ends. RecG also plays a role in stabilising joint molecules formed during DSBR...
February 2, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28155199/molecular-breeding-of-saccharomyces-cerevisiae-with-high-rna-content-by-harnessing-essential-ribosomal-rna-transcription-regulator
#15
Yu Sasano, Takahiro Kariya, Shogo Usugi, Minetaka Sugiyama, Satoshi Harashima
As yeast is commonly used for RNA production, it is industrially important to breed strains with high RNA contents. The upstream activating factor (UAF) plays an important role in transcription of ribosomal RNA (rRNA), a major constituent of intracellular RNA species. Here, we targeted the essential rRNA transcription regulator Rrn5 of Saccharomyces cerevisiae, a component of the UAF complex, and disrupted the genomic RRN5 gene using a helper plasmid carrying an RRN5 gene. Then we isolated nine suppressor mutants (Sup mutants) of RRN5 gene disruption, causing deficiency in rRNA transcription...
December 2017: AMB Express
https://www.readbyqxmd.com/read/28153919/function-of-the-plant-dna-polymerase-epsilon-in-replicative-stress-sensing-a-genetic-analysis
#16
Jose-Antonio Pedroza-Garcia, Christelle Mazubert, Ivan Del Olmo, Mickael Bourge, Séverine Domenichini, Rémi Bounon, Zakia Tariq, Etienne Delannoy, Manuel Piñeiro, Jose A Jarillo, Catherine Bergounioux, Moussa Benhamed, Cécile Raynaud
Faithful transmission of the genetic information is essential in all living organisms. DNA replication is therefore a critical step of cell proliferation, because of the potential occurrence of replication errors or DNA damage when progression of a replication fork is hampered causing replicative stress. Like other types of DNA damage, replicative stress activates the DNA Damage Response (DDR) a signaling cascade allowing cell cycle arrest and repair of lesions. The replicative DNA polymerase ε (Pol ε) was shown to activate the S-phase checkpoint in yeast in response to replicative stress, but whether this mechanism functions in multicellular eukaryotes remains unclear...
February 2, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28146113/solving-the-telomere-replication-problem
#17
REVIEW
Laetitia Maestroni, Samah Matmati, Stéphane Coulon
Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity...
January 31, 2017: Genes
https://www.readbyqxmd.com/read/28133760/capitalizing-on-disaster-establishing-chromatin-specificity-behind-the-replication-fork
#18
Srinivas Ramachandran, Kami Ahmad, Steven Henikoff
Eukaryotic genomes are packaged into nucleosomal chromatin, and genomic activity requires the precise localization of transcription factors, histone modifications and nucleosomes. Classic work described the progressive reassembly and maturation of bulk chromatin behind replication forks. More recent proteomics has detailed the molecular machines that accompany the replicative polymerase to promote rapid histone deposition onto the newly replicated DNA. However, localized chromatin features are transiently obliterated by DNA replication every S phase of the cell cycle...
January 30, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28129339/re-wiring-of-energy-metabolism-promotes-viability-during-hyperreplication-stress-in-e-coli
#19
Godefroid Charbon, Christopher Campion, Siu Hung Joshua Chan, Louise Bjørn, Allan Weimann, Luís Cláudio Nascimento da Silva, Peter Ruhdal Jensen, Anders Løbner-Olesen
Chromosome replication in Escherichia coli is initiated by DnaA. DnaA binds ATP which is essential for formation of a DnaA-oriC nucleoprotein complex that promotes strand opening, helicase loading and replisome assembly. Following initiation, DnaAATP is converted to DnaAADP primarily by the Regulatory Inactivation of DnaA process (RIDA). In RIDA deficient cells, DnaAATP accumulates leading to uncontrolled initiation of replication and cell death by accumulation of DNA strand breaks. Mutations that suppress RIDA deficiency either dampen overinitiation or permit growth despite overinitiation...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28126821/rpa-binds-histone-h3-h4-and-functions-in-dna-replication-coupled-nucleosome-assembly
#20
Shaofeng Liu, Zhiyun Xu, He Leng, Pu Zheng, Jiayi Yang, Kaifu Chen, Jianxun Feng, Qing Li
DNA replication-coupled nucleosome assembly is essential to maintain genome integrity and retain epigenetic information. Multiple involved histone chaperones have been identified, but how nucleosome assembly is coupled to DNA replication remains elusive. Here we show that replication protein A (RPA), an essential replisome component that binds single-stranded DNA, has a role in replication-coupled nucleosome assembly. RPA directly binds free H3-H4. Assays using a synthetic sequence that mimics freshly unwound single-stranded DNA at replication fork showed that RPA promotes DNA-(H3-H4) complex formation immediately adjacent to double-stranded DNA...
January 27, 2017: Science
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