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Replication fork

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https://www.readbyqxmd.com/read/29157061/the-dna-pol-%C3%AF%C2%B5-stimulatory-activity-of-mrc1-is-modulated-by-phosphorylation
#1
Zhong-Xin Zhang, Jingjing Zhang, Qinhong Cao, Judith L Campbell, Huiqiang Lou
DNA replication checkpoint (Mec1-Mrc1-Rad53 in budding yeast) is an evolutionarily conserved surveillance system to ensure proper DNA replication and genome stability in all eukaryotes. Compared to its well-known function as a mediator of replication checkpoint, the exact role of Mrc1 as a component of normal replication forks remains relatively unclear. In this study, we provide in vitro biochemical evidence to support that yeast Mrc1 is able to enhance the activity of DNA polymerase ϵ (Pol ϵ), the major leading strand replicase...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29156764/the-neil1-g83d-germline-dna-glycosylase-variant-induces-genomic-instability-and-cellular-transformation
#2
Heather A Galick, Carolyn G Marsden, Scott Kathe, Julie A Dragon, Lindsay Volk, Antonia A Nemec, Susan S Wallace, Aishwarya Prakash, Sylvie Doublié, Joann B Sweasy
Base excision repair (BER) is a key genome maintenance pathway. The NEIL1 DNA glycosylase recognizes oxidized bases, and likely removes damage in advance of the replication fork. The rs5745906 SNP of the NEIL1 gene is a rare human germline variant that encodes the NEIL1 G83D protein, which is devoid of DNA glycosylase activity. Here we show that expression of G83D NEIL1 in MCF10A immortalized but non-transformed mammary epithelial cells leads to replication fork stress. Upon treatment with hydrogen peroxide, we observe increased levels of stalled replication forks in cells expressing G83D NEIL1 versus cells expressing the wild-type (WT) protein...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29155954/the-human-papillomavirus-dna-helicase-e1-binds-stimulates-and-confers-processivity-to-cellular-dna-polymerase-epsilon
#3
Michaelle Chojnacki, Thomas Melendy
The papillomavirus (PV) helicase protein E1 recruits components of the cellular DNA replication machinery to the PV replication fork, such as Replication Protein A (RPA), DNA polymerase α-primase (pol α) and topoisomerase I (topo I). Here we show that E1 binds to DNA polymerase ϵ (pol ϵ) and dramatically stimulates the DNA synthesis activity of pol ϵ. This stimulation of pol ϵ by E1 is highly specific and occurs even in the absence of the known pol ϵ cofactors Replication Factor C (RFC), Proliferating Cell Nuclear Antigen (PCNA) and RPA...
November 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29153834/precise-editing-at-dna-replication-forks-enables-multiplex-genome-engineering-in-eukaryotes
#4
Edward M Barbieri, Paul Muir, Benjamin O Akhuetie-Oni, Christopher M Yellman, Farren J Isaacs
We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids the creation of double-strand DNA breaks, enabling precise chromosome modifications at single base-pair resolution with an efficiency of >40%, without unintended mutagenic changes at the targeted genetic loci. We observed the simultaneous incorporation of up to 12 oligonucleotides with as many as 60 targeted mutations in one transformation...
November 15, 2017: Cell
https://www.readbyqxmd.com/read/29149299/twj-screen-an-isothermal-screening-assay-to-assess-ligand-dna-junction-interactions-in-vitro
#5
Ludivine Guyon, Marc Pirrotta, Katerina Duskova, Anton Granzhan, Marie-Paule Teulade-Fichou, David Monchaud
The quest for chemicals able to operate at selected genomic loci in a spatiotemporally controlled manner is desirable to create manageable DNA damages. Mounting evidence now shows that alternative DNA structures, including G-quadruplexes and branched DNA (or DNA junctions), might hamper proper progression of replication fork, thus triggering DNA damages and genomic instability. Therefore, small molecules that stabilize these DNA structures are currently scrutinized as a promising way to create genomic defects that cannot be dealt with properly by cancer cells...
November 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29145865/the-endonuclease-eepd1-mediates-synthetic-lethality-in-rad52-depleted-brca1-mutant-breast-cancer-cells
#6
Robert Hromas, Hyun-Suk Kim, Gurjit Sidhu, Elizabeth Williamson, Aruna Jaiswal, Taylor A Totterdale, Jocelyn Nole, Suk-Hee Lee, Jac A Nickoloff, Kimi Y Kong
BACKGROUND: Proper repair and restart of stressed replication forks requires intact homologous recombination (HR). HR at stressed replication forks can be initiated by the 5' endonuclease EEPD1, which cleaves the stalled replication fork. Inherited or acquired defects in HR, such as mutations in breast cancer susceptibility protein-1 (BRCA1) or BRCA2, predispose to cancer, including breast and ovarian cancers. In order for these HR-deficient tumor cells to proliferate, they become addicted to a bypass replication fork repair pathway mediated by radiation repair protein 52 (RAD52)...
November 16, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29141206/role-of-the-pif1-pcna-complex-in-pol-%C3%AE-dependent-strand-displacement-dna-synthesis-and-break-induced-replication
#7
Olga Buzovetsky, Youngho Kwon, Nhung Tuyet Pham, Claire Kim, Grzegorz Ira, Patrick Sung, Yong Xiong
The S. cerevisiae Pif1 helicase functions with DNA polymerase (Pol) δ in DNA synthesis during break-induced replication (BIR), a conserved pathway responsible for replication fork repair and telomere recombination. Pif1 interacts with the DNA polymerase processivity clamp PCNA, but the functional significance of the Pif1-PCNA complex remains to be elucidated. Here, we solve the crystal structure of PCNA in complex with a non-canonical PCNA-interacting motif in Pif1. The structure guides the construction of a Pif1 mutant that is deficient in PCNA interaction...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29138305/manipulating-the-bacterial-cell-cycle-and-cell-size-by-titrating-the-expression-of-ribonucleotide-reductase
#8
Manlu Zhu, Xiongfeng Dai, Weilun Guo, Zengxiang Ge, Mingxuan Yang, Haikuan Wang, Yi-Ping Wang
Understanding how bacteria coordinate growth with cell cycle events to maintain cell size homeostasis remains a grand challenge in biology. The period of chromosome replication (C period) is a key stage in the bacterial cell cycle. However, the mechanism of in vivo regulation of the C period remains unclear. In this study, we found that titration of the expression of ribonucleotide reductase (RNR), which changes the intracellular deoxynucleoside triphosphate (dNTP) pools, enables significant perturbations of the C period, leading to a substantial change in cell size and DNA content...
November 14, 2017: MBio
https://www.readbyqxmd.com/read/29133300/the-importance-of-satellite-sequence-repression-for-genome-stability
#9
Peter Zeller, Susan M Gasser
Up to two-thirds of eukaryotic genomes consist of repetitive sequences, which include both transposable elements and tandemly arranged simple or satellite repeats. Whereas extensive progress has been made toward understanding the danger of and control over transposon expression, only recently has it been recognized that DNA damage can arise from satellite sequence transcription. Although the structural role of satellite repeats in kinetochore function and end protection has long been appreciated, it has now become clear that it is not only these functions that are compromised by elevated levels of transcription...
November 13, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29129641/cohesin-ubiquitylation-and-mobilization-facilitate-stalled-replication-fork-dynamics
#10
Camilla Frattini, Sara Villa-Hernández, Grazia Pellicanò, Rachel Jossen, Yuki Katou, Katsuhiko Shirahige, Rodrigo Bermejo
Replication fork integrity is challenged in conditions of stress and protected by the Mec1/ATR checkpoint to preserve genome stability. Still poorly understood in fork protection is the role played by the structural maintenance of chromosomes (SMC) cohesin complex. We uncovered a role for the Rsp5(Bul2) ubiquitin ligase in promoting survival to replication stress by preserving stalled fork integrity. Rsp5(Bul2) physically interacts with cohesin and the Mec1 kinase, thus promoting checkpoint-dependent cohesin ubiquitylation and cohesin-mediated fork protection...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29125140/mouse-embryonic-stem-cells-have-increased-capacity-for-replication-fork-restart-driven-by-the-specific-filia-floped-protein-complex
#11
Bo Zhao, Weidao Zhang, Yixian Cun, Jingzheng Li, Yan Liu, Jing Gao, Hongwen Zhu, Hu Zhou, Rugang Zhang, Ping Zheng
Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative medicine. It is therefore important to understand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonic stem cells (ESCs) are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks, therefore maintaining genomic stability...
November 10, 2017: Cell Research
https://www.readbyqxmd.com/read/29123096/atr-kinase-inhibition-induces-unscheduled-origin-firing-through-a-cdc7-dependent-association-between-gins-and-and-1
#12
Tatiana Moiseeva, Brian Hood, Sandy Schamus, Mark J O'Connor, Thomas P Conrads, Christopher J Bakkenist
ATR kinase activity slows replication forks and prevents origin firing in damaged cells. Here we describe proteomic analyses that identified mechanisms through which ATR kinase inhibitors induce unscheduled origin firing in undamaged cells. ATR-Chk1 inhibitor-induced origin firing is mediated by Cdc7 kinase through previously undescribed phosphorylations on GINS that induce an association between GINS and And-1. ATR-Chk1 inhibitor-induced origin firing is blocked by prior exposure to DNA damaging agents showing that the prevention of origin firing does not require ongoing ATR activity...
November 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/29123070/redox-sensitive-alteration-of-replisome-architecture-safeguards-genome-integrity
#13
Kumar Somyajit, Rajat Gupta, Hana Sedlackova, Kai John Neelsen, Fena Ochs, Maj-Britt Rask, Chunaram Choudhary, Jiri Lukas
DNA replication requires coordination between replication fork progression and deoxynucleotide triphosphate (dNTP)-generating metabolic pathways. We find that perturbation of ribonucleotide reductase (RNR) in humans elevates reactive oxygen species (ROS) that are detected by peroxiredoxin 2 (PRDX2). In the oligomeric state, PRDX2 forms a replisome-associated ROS sensor, which binds the fork accelerator TIMELESS when exposed to low levels of ROS. Elevated ROS levels generated by RNR attenuation disrupt oligomerized PRDX2 to smaller subunits, whose dissociation from chromatin enforces the displacement of TIMELESS from the replisome...
November 10, 2017: Science
https://www.readbyqxmd.com/read/29123052/the-need-to-regulate-replication-fork-speed
#14
Belén Gómez-González, Andrés Aguilera
No abstract text is available yet for this article.
November 10, 2017: Science
https://www.readbyqxmd.com/read/29119272/interaction-of-the-saccharomyces-cerevisiae-ring-domain-protein-nse1-with-nse3-and-the-smc5-6-complex-is-required-for-chromosome-replication-and-stability
#15
Saima Wani, Neelam Maharshi, Deepash Kothiwal, Lakshmi Mahendrawada, Raju Kalaivani, Shikha Laloraya
Genomic stability is maintained by the concerted actions of numerous protein complexes that participate in chromosomal duplication, repair, and segregation. The Smc5/6 complex is an essential multi-subunit complex crucial for repair of DNA double-strand breaks. Two of its subunits, Nse1 and Nse3, are homologous to the RING-MAGE complexes recently described in human cells. We investigated the contribution of the budding yeast Nse1 RING-domain by isolating a mutant nse1-103 bearing substitutions in conserved Zinc-coordinating residues of the RING-domain that is hypersensitive to genotoxic stress and temperature...
November 8, 2017: Current Genetics
https://www.readbyqxmd.com/read/29119271/rnr1-s-role-in-telomere-elongation-cannot-be-replaced-by-rnr3-a-role-beyond-dntps
#16
REVIEW
André Maicher, Martin Kupiec
Telomeres, the nucleoprotein complexes at the end of eukaryotic chromosomes, protect them from degradation and ensure the replicative capacity of cells. In most human tumors and in budding yeast, telomere length is maintained by the activity of telomerase, an enzyme that adds dNTPs according to an internal RNA template. The dNTPs are generated with the help of the ribonucleotide reductase (RNR) complex. We have recently generated strains lacking the large subunit of RNR, Rnr1, which were kept viable by the expression of RNR complexes containing the Rnr1 homolog, Rnr3...
November 8, 2017: Current Genetics
https://www.readbyqxmd.com/read/29109278/coordinated-regulation-of-heterochromatin-inheritance-by-dpb3-dpb4-complex
#17
Haijin He, Yang Li, Qianhua Dong, An-Yun Chang, Feng Gao, Zhongxuan Chi, Min Su, Faben Zhang, Hyoju Ban, Rob Martienssen, Yu-Hang Chen, Fei Li
During DNA replication, chromatin is disrupted ahead of the replication fork, and epigenetic information must be restored behind the fork. How epigenetic marks are inherited through DNA replication remains poorly understood. Histone H3 lysine 9 (H3K9) methylation and histone hypoacetylation are conserved hallmarks of heterochromatin. We previously showed that the inheritance of H3K9 methylation during DNA replication depends on the catalytic subunit of DNA polymerase epsilon, Cdc20. Here we show that the histone-fold subunit of Pol epsilon, Dpb4, interacts an uncharacterized small histone-fold protein, SPCC16C4...
November 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29108427/what-is-all-this-fuss-about-tus-comparison-of-recent-findings-from-biophysical-and-biochemical-experiments
#18
Bojk A Berghuis, Vlad-Stefan Raducanu, Mohamed M Elshenawy, Slobodan Jergic, Martin Depken, Nicholas E Dixon, Samir M Hamdan, Nynke H Dekker
Synchronizing the convergence of the two-oppositely moving DNA replication machineries at specific termination sites is a tightly coordinated process in bacteria. In Escherichia coli, a "replication fork trap" - found within a chromosomal region where forks are allowed to enter but not leave - is set by the protein-DNA roadblock Tus-Ter. The exact sequence of events by which Tus-Ter blocks replisomes approaching from one direction but not the other has been the subject of controversy for many decades. Specific protein-protein interactions between the nonpermissive face of Tus and the approaching helicase were challenged by biochemical and structural studies...
November 6, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29106372/53bp1-and-brca1-control-pathway-choice-for-stalled-replication-restart
#19
Yixi Xu, Shaokai Ning, Zheng Wei, Ran Xu, Xinlin Xu, Mengtan Xing, Rong Guo, Dongyi Xu
The cellular pathways that restart stalled replication forks are essential for genome stability and tumor prevention. However, how many of these pathways exist in cells and how these pathways are selectively activated remain unclear. Here, we describe two major fork restart pathways, and demonstrate that their selection is governed by 53BP1 and BRCA1, which are known to control the pathway choice to repair double-strand DNA breaks (DSBs). Specifically, 53BP1 promotes a fork cleavage-free pathway, whereas BRCA1 facilitates a break-induced replication (BIR) pathway coupled with SLX-MUS complex-mediated fork cleavage...
November 6, 2017: ELife
https://www.readbyqxmd.com/read/29103969/differentiation-of-human-induced-pluripotent-or-embryonic-stem-cells-decreases-the-dna-damage-repair-by-homologous-recombination
#20
Kalpana Mujoo, Raj K Pandita, Anjana Tiwari, Vijay Charaka, Sharmistha Chakraborty, Dharmendra Kumar Singh, Shashank Hambarde, Walter N Hittelman, Nobuo Horikoshi, Clayton R Hunt, Kum Kum Khanna, Alexander Y Kots, E Brian Butler, Ferid Murad, Tej K Pandita
The nitric oxide (NO)-cyclic GMP pathway contributes to human stem cell differentiation, but NO free radical production can also damage DNA, necessitating a robust DNA damage response (DDR) to ensure cell survival. How the DDR is affected by differentiation is unclear. Differentiation of stem cells, either inducible pluripotent or embryonic derived, increased residual DNA damage as determined by γ-H2AX and 53BP1 foci, with increased S-phase-specific chromosomal aberration after exposure to DNA-damaging agents, suggesting reduced homologous recombination (HR) repair as supported by the observation of decreased HR-related repair factor foci formation (RAD51 and BRCA1)...
November 14, 2017: Stem Cell Reports
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