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https://www.readbyqxmd.com/read/28535251/mms1-binds-to-g-rich-regions-in-saccharomyces-cerevisiae-and-influences-replication-and-genome-stability
#1
Katharina Wanzek, Eike Schwindt, John A Capra, Katrin Paeschke
The regulation of replication is essential to preserve genome integrity. Mms1 is part of the E3 ubiquitin ligase complex that is linked to replication fork progression. By identifying Mms1 binding sites genome-wide in Saccharomyces cerevisiae we connected Mms1 function to genome integrity and replication fork progression at particular G-rich motifs. This motif can form G-quadruplex (G4) structures in vitro. G4 are stable DNA structures that are known to impede replication fork progression. In the absence of Mms1, genome stability is at risk at these G-rich/G4 regions as demonstrated by gross chromosomal rearrangement assays...
May 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28534480/molecular-basis-for-primpol-recruitment-to-replication-forks-by-rpa
#2
Thomas A Guilliam, Nigel C Brissett, Aaron Ehlinger, Benjamin A Keen, Peter Kolesar, Elaine M Taylor, Laura J Bailey, Howard D Lindsay, Walter J Chazin, Aidan J Doherty
DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase-polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28527403/interplay-between-bacillus-subtilis-recd2-and-the-recg-or-ruvab-helicase-in-recombinational-repair
#3
Rubén Torres, Hector Romero, Violeta Rodríguez-Cerrato, Juan C Alonso
Bacillus subtilis AddAB, RecS, RecQ, PcrA, HelD, DinG, RecG, RuvAB, PriA and RecD2 are genuine recombinational repair enzymes, but the biological role of RecD2 is poorly defined. A ΔrecD2 mutation sensitizes cells to DNA-damaging agents that stall or collapse replication forks. We found that this ΔrecD2 mutation impaired growth, and that a mutation in the pcrA gene (pcrA596) relieved this phenotype. The ΔrecD2 mutation was not epistatic to ΔaddAB, ΔrecQ, ΔrecS, ΔhelD, pcrA596 and ΔdinG, but epistatic to recA...
May 12, 2017: DNA Repair
https://www.readbyqxmd.com/read/28525744/ctf4-prevents-genome-rearrangements-by-suppressing-dna-double-strand-break-formation-and-its-end-resection-at-arrested-replication-forks
#4
Mariko Sasaki, Takehiko Kobayashi
Arrested replication forks lead to DNA double-strand breaks (DSBs), which are a major source of genome rearrangements. Yet DSB repair in the context of broken forks remains poorly understood. Here we demonstrate that DSBs that are formed at arrested forks in the budding yeast ribosomal RNA gene (rDNA) locus are normally repaired by pathways dependent on the Mre11-Rad50-Xrs2 complex but independent of HR. HR is also dispensable for DSB repair at stalled forks at tRNA genes. In contrast, in cells lacking the core replisome component Ctf4, DSBs are formed more frequently, and these DSBs undergo end resection and HR-mediated repair that is prone to rDNA hyper-amplification; this highlights Ctf4 as a key regulator of DSB end resection at arrested forks...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28515154/progerin-sequestration-of-pcna-promotes-replication-fork-collapse-and-mislocalization-of-xpa-in-laminopathy-related-progeroid-syndromes
#5
Benjamin A Hilton, Ji Liu, Brian M Cartwright, Yiyong Liu, Maya Breitman, Youjie Wang, Rowdy Jones, Hui Tang, Antonio Rusinol, Phillip R Musich, Yue Zou
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin...
May 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28511132/activity-and-in-vivo-dynamics-of-bacillus-subtilis-disa-are-affected-by-rada-sms-and-by-holliday-junction-processing-proteins
#6
Carolina Gándara, Daniella K C de Lucena, Rubén Torres, Ester Serrano, Stephan Altenburger, Peter L Graumann, Juan C Alonso
Bacillus subtilis c-di-AMP synthase DisA and RecA-related RadA/Sms are involved in the repair of DNA damage in exponentially growing cells. We provide genetic evidence that DisA or RadA/Sms is epistatic to the branch migration translocase (BMT) RecG and the Holliday junction (HJ) resolvase RecU in response to DNA damage. We provide genetic evidence damage. Functional DisA-YFP formed dynamic foci in exponentially growing cells, which moved through the nucleoids at a speed compatible with a DNA-scanning mode...
May 5, 2017: DNA Repair
https://www.readbyqxmd.com/read/28510759/an-intact-mcm10-coiled-coil-interaction-surface-is-important-for-origin-melting-helicase-assembly-and-the-recruitment-of-pol-%C3%AE-to-mcm2-7
#7
Patricia Perez-Arnaiz, Irina Bruck, Max K Colbert, Daniel L Kaplan
Mcm10 is an essential eukaryotic factor required for DNA replication. The replication fork helicase is composed of Cdc45, Mcm2-7 and GINS (CMG). DDK is an S-phase-specific kinase required for replication initiation, and the DNA primase-polymerase in eukaryotes is pol α. Mcm10 forms oligomers in vitro, mediated by the coiled-coil domain at the N-terminal region of the protein. We characterized an Mcm10 mutant at the N-terminal Domain (NTD), Mcm10-4A, defective for self-interaction. We found that the Mcm10-4A mutant was defective for stimulating DDK phosphorylation of Mcm2, binding to eighty-nucleotide ssDNA, and recruiting pol α to Mcm2-7 in vitro...
May 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28506294/hssb1-associates-with-and-promotes-stability-of-the-blm-helicase
#8
Laura V Croft, Nicholas W Ashton, Nicolas Paquet, Emma Bolderson, Kenneth J O'Byrne, Derek J Richard
BACKGROUND: Maintenance of genome stability is critical in human cells. Mutations in or loss of genome stability pathways can lead to a number of pathologies including cancer. hSSB1 is a critical DNA repair protein functioning in the repair and signalling of stalled DNA replication forks, double strand DNA breaks and oxidised DNA lesions. The BLM helicase is central to the repair of both collapsed DNA replication forks and double strand DNA breaks by homologous recombination. RESULTS: In this study, we demonstrate that hSSB1 and BLM helicase form a complex in cells and the interaction is altered in response to ionising radiation (IR)...
May 15, 2017: BMC Molecular Biology
https://www.readbyqxmd.com/read/28505413/protein-displacement-by-herpes-helicase-primase-and-the-key-role-of-ul42-during-helicase-coupled-dna-synthesis-by-the-herpes-polymerase
#9
Sarah Michelle Dickerson, Robert D Kuchta
The herpes helicase-primase (UL5-UL8-UL52) very inefficiently unwinds double stranded DNA. To better understand the mechanistic consequences of this inefficiency, we investigated protein displacement activity by UL5-UL8-UL52, as well as the impact of coupling DNA synthesis by the herpes polymerase with helicase activity. While the helicase can displace proteins bound to the lagging strand template, bound proteins significantly impede helicase activity. Remarkably, UL5-UL8-UL52, an extremely inefficient helicase, disrupts the exceptionally tight interaction between streptavidin and biotin on the lagging strand template...
May 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28501701/radb-acts-in-homologous-recombination-in-the-archaeon-haloferax-volcanii-consistent-with-a-role-as-recombination-mediator
#10
Kayleigh Wardell, Sam Haldenby, Nathan Jones, Susan Liddell, Greg H P Ngo, Thorsten Allers
Homologous recombination plays a central role in the repair of double-strand DNA breaks, the restart of stalled replication forks and the generation of genetic diversity. Regulation of recombination is essential since defects can lead to genome instability and chromosomal rearrangements. Strand exchange is a key step of recombination - it is catalysed by RecA in bacteria, Rad51/Dmc1 in eukaryotes and RadA in archaea. RadB, a paralogue of RadA, is present in many archaeal species. RadB has previously been proposed to function as a recombination mediator, assisting in RadA-mediated strand exchange...
April 26, 2017: DNA Repair
https://www.readbyqxmd.com/read/28501329/eukaryotic-dna-replication-orchestrated-action-of-multi-subunit-protein-complexes
#11
REVIEW
Sukhyun Kang, Mi-Sun Kang, Eunjin Ryu, Kyungjae Myung
Genome duplication is an essential process to preserve genetic information between generations. The eukaryotic cell cycle is composed of functionally distinct phases: G1, S, G2, and M. One of the key replicative proteins that participate at every stage of DNA replication is the Mcm2-7 complex, a replicative helicase. In the G1 phase, inactive Mcm2-7 complexes are loaded on the replication origins by replication-initiator proteins, ORC and Cdc6. Two kinases, S-CDK and DDK, convert the inactive origin-loaded Mcm2-7 complex to an active helicase, the CMG complex in the S phase...
May 1, 2017: Mutation Research
https://www.readbyqxmd.com/read/28496054/days-weaving-the-lagging-strand-synthesis-of-dna-a-personal-recollection-of-the-discovery-of-okazaki-fragments-and-studies-on-discontinuous-replication-mechanism
#12
Tsuneko Okazaki
At DNA replication forks, the overall growth of the antiparallel two daughter DNA chains appears to occur 5'-to-3' direction in the leading-strand and 3'-to-5' direction in the lagging-strand using enzyme system only able to elongate 5'-to-3' direction, and I describe in this review how we have analyzed and proved the lagging strand multistep synthesis reactions, called Discontinuous Replication Mechanism, which involve short RNA primer synthesis, primer-dependent short DNA chains (Okazaki fragments) synthesis, primer removal from the Okazaki fragments and gap filling between Okazaki fragments by RNase H and DNA polymerase I, and long lagging strand formation by joining between Okazaki fragments with DNA ligase...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/28490629/pharmacological-targeting-of-rad6-enzyme-mediated-translesion-synthesis-overcomes-resistance-to-platinum-based-drugs
#13
Matthew A Sanders, Brittany Haynes, Pratima Nangia-Makker, Lisa A Polin, Malathy P Shekhar
Platinum drug-induced crosslink repair requires the concerted activities of translesion synthesis (TLS), Fanconi anemia (FA) and homologous recombination repair pathways. The E2 ubiquitin-conjugating enzyme Rad6 is essential for TLS. Here, we show that Rad6 plays a universal role in platinum-based drug tolerance. Using a novel Rad6-selective small molecule inhibitor (SMI#9) targeting the Rad6 catalytic site, we demonstrate that SMI#9 potentiates the sensitivities of cancer cells with innate or acquired cisplatin or oxaliplatin resistance...
May 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28487407/acute-inactivation-of-the-replicative-helicase-in-human-cells-triggers-mcm8-9-dependent-dna-synthesis
#14
Toyoaki Natsume, Kohei Nishimura, Sheroy Minocherhomji, Rahul Bhowmick, Ian D Hickson, Masato T Kanemaki
DNA replication fork progression can be disrupted at difficult to replicate loci in the human genome, which has the potential to challenge chromosome integrity. This replication fork disruption can lead to the dissociation of the replisome and the formation of DNA damage. To model the events stemming from replisome dissociation during DNA replication perturbation, we used a degron-based system for inducible proteolysis of a subunit of the replicative helicase. We show that MCM2-depleted cells activate a DNA damage response pathway and generate replication-associated DNA double-strand breaks (DSBs)...
May 9, 2017: Genes & Development
https://www.readbyqxmd.com/read/28483909/progerin-induced-replication-stress-facilitates-premature-senescence-in-hutchinson-gilford-progeria-syndrome
#15
Keith Wheaton, Denise Campuzano, Weili Ma, Michal Sheinis, Brandon Ho, Grant W Brown, Samuel Benchimol
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here, we show that young, cycling HGPS fibroblasts, exhibit chronic DNA damage primarily in S phase as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA altering its distribution away from replicating DNA in HGPS cells leading to γH2AX formation, ATR activation and RPA Ser33 phosphorylation...
May 8, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28477108/assaying-for-radioresistant-dna-synthesis-the-hallmark-feature-of-the-intra-s-phase-checkpoint-using-a-dna-fiber-technique
#16
Amanda W Kijas, Martin F Lavin
During S-phase the cell replicates its DNA which is critical to maintaining the integrity of the genome and cell survival amidst damaging events. The cell is equipped with a series of checkpoints to slow progress throughout the cycle and facilitate DNA repair. Ataxia telangiectasia mutated (ATM), defective in the human genetic disorder ataxia-telangiectasia (A-T), is the key to initiating a signaling cascade activating the intra-S-phase checkpoint. This was first identified in A-T cells as radioresistant DNA synthesis using (14)C thymidine and (3)H thymidine to pulse label replicating cells before and after damage...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28476890/sequence-imperfections-and-base-triplet-recognition-by-the-rad51-reca-family-of-recombinases
#17
Ja Yil Lee, Justin B Steinfeld, Zhi Qi, YoungHo Kwon, Patrick Sung, Eric C Greene
Homologous recombination plays key roles in double strand break repair, rescue and repair of stalled replication forks, and meiosis. The broadly conserved Rad51/RecA family of recombinases catalyze the DNA strand invasion reaction that takes place during homologous recombination. We have established ssDNA curtain assays for measuring individual base triplet steps during the early stages of strand invasion. Here we examine how base triplet stepping by RecA, Rad51, and Dmc1 is affected by DNA sequence imperfections, such as single and multiple mismatches, abasic sites, and single nucleotide insertions...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28475874/unprotected-replication-forks-are-converted-into-mitotic-sister-chromatid-bridges
#18
Anissia Ait Saada, Ana Teixeira-Silva, Ismail Iraqui, Audrey Costes, Julien Hardy, Giulia Paoletti, Karine Fréon, Sarah A E Lambert
Replication stress and mitotic abnormalities are key features of cancer cells. Temporarily paused forks are stabilized by the intra-S phase checkpoint and protected by the association of Rad51, which prevents Mre11-dependent resection. However, if a fork becomes dysfunctional and cannot resume, this terminally arrested fork is rescued by a converging fork to avoid unreplicated parental DNA during mitosis. Alternatively, dysfunctional forks are restarted by homologous recombination. Using fission yeast, we report that Rad52 and the DNA binding activity of Rad51, but not its strand-exchange activity, act to protect terminally arrested forks from unrestrained Exo1-nucleolytic activity...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475600/a-new-role-for-rrm3-in-repair-of-replication-born-dna-breakage-by-sister-chromatid-recombination
#19
Sandra Muñoz-Galván, María García-Rubio, Pedro Ortega, Jose F Ruiz, Sonia Jimeno, Benjamin Pardo, Belén Gómez-González, Andrés Aguilera
Replication forks stall at different DNA obstacles such as those originated by transcription. Fork stalling can lead to DNA double-strand breaks (DSBs) that will be preferentially repaired by homologous recombination when the sister chromatid is available. The Rrm3 helicase is a replisome component that promotes replication upon fork stalling, accumulates at highly transcribed regions and prevents not only transcription-induced replication fork stalling but also transcription-associated hyper-recombination...
May 5, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28474797/a-mechanistic-study-of-helicases-with-magnetic-traps
#20
REVIEW
Samar Hodeib, Saurabh Raj, M Manosas, Weiting Zhang, Debjani Bagchi, Bertrand Ducos, Francesca Fiorini, Joanne Kanaan, Hervé Le Hir, Jean-François Allemand, David Bensimon, Vincent Croquette
Helicases are a broad family of enzymes that separate nucleic acid double strand structures (DNA/DNA, DNA/RNA or RNA/RNA) and thus are essential to DNA replication and the maintenance of nucleic acid integrity. We review the picture that has emerged from single molecule studies of the mechanisms of DNA and RNA helicases and their interactions with other proteins. Many features have been uncovered by these studies that were obscured by bulk studies, such as DNA strands switching, mechanical (rather than biochemical) coupling between helicases and polymerases, helicase-induced re-hybridization and stalled fork rescue...
May 5, 2017: Protein Science: a Publication of the Protein Society
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