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https://www.readbyqxmd.com/read/29789314/inhibition-of-atr-acutely-sensitizes-acute-myeloid-leukemia-cells-to-nucleoside-analogs-that-target-ribonucleotide-reductase
#1
Sarah E Fordham, Helen J Blair, Claire J Elstob, Ruth Plummer, Yvette Drew, Nicola J Curtin, Olaf Heidenreich, Deepali Pal, David Jamieson, Catherine Park, John Pollard, Scott Fields, Paul Milne, Graham H Jackson, Helen J Marr, Tobias Menne, Gail L Jones, James M Allan
The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression...
May 22, 2018: Blood Advances
https://www.readbyqxmd.com/read/29788478/a-minimal-threshold-of-fancj-helicase-activity-is-required-for-its-response-to-replication-stress-or-double-strand-break-repair
#2
Sanjay Kumar Bharti, Joshua A Sommers, Sanket Awate, Marina A Bellani, Irfan Khan, Lynda Bradley, Graeme A King, Yeonee Seol, Venkatasubramanian Vidhyasagar, Yuliang Wu, Takuye Abe, Koji Kobayashi, Kazuo Shin-Ya, Hiroyuki Kitao, Marc S Wold, Dana Branzei, Keir C Neuman, Robert M Brosh
Fanconi Anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer. Of over 20 FA-linked genes, FANCJ uniquely encodes a DNA helicase and mutations are also associated with breast and ovarian cancer. fancj-/- cells are sensitive to DNA interstrand cross-linking (ICL) and replication fork stalling drugs. We delineated the molecular defects of two FA patient-derived FANCJ helicase domain mutations. FANCJ-R707C was compromised in dimerization and helicase processivity, whereas DNA unwinding by FANCJ-H396D was barely detectable...
May 21, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29777036/pol%C3%AE-a-y-family-translesion-synthesis-polymerase-promotes-cellular-tolerance-of-myc-induced-replication-stress
#3
Kiminori Kurashima, Takayuki Sekimoto, Tsukasa Oda, Tsuyoshi Kawabata, Fumio Hanaoka, Takayuki Yamashita
Growth of precancerous and cancer cells relies on their tolerance of oncogene-induced replication stress (RS). Translesion synthesis (TLS) plays an essential role in cellular tolerance of various types of RS and bypasses replication barriers by employing specialized polymerases. However, limited information is available about the role of TLS polymerases in oncogene-induced RS. Here, we report that Polη, a Y-family TLS polymerase, promotes cellular tolerance of Myc-induced RS. Polη was recruited to Myc-induced RS sites, and Polη depletion enhanced the Myc-induced slowing and stalling of replication forks and the subsequent generation of double-strand breaks (DSBs)...
May 18, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29775579/a-mad2-mediated-translational-regulatory-mechanism-promoting-s-phase-cyclin-synthesis-controls-origin-firing-and-survival-to-replication-stress
#4
Sophie Gay, Daniele Piccini, Christopher Bruhn, Sara Ricciardi, Paolo Soffientini, Walter Carotenuto, Stefano Biffo, Marco Foiani
Cell survival to replication stress depends on the activation of the Mec1ATR -Rad53 checkpoint response that protects the integrity of stalled forks and controls the origin firing program. Here we found that Mad2, a member of the spindle assembly checkpoint (SAC), contributes to efficient origin firing and to cell survival in response to replication stress. We show that Rad53 and Mad2 promote S-phase cyclin expression through different mechanisms: while Rad53 influences Clb5,6 degradation, Mad2 promotes their protein synthesis...
May 17, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29775464/biochemical-characterization-of-recbcd-enzyme-from-an-antarctic-pseudomonas-species-and-identification-of-its-cognate-chi-%C3%AF-sequence
#5
Theetha L Pavankumar, Anurag K Sinha, Malay K Ray
Pseudomonas syringae Lz4W RecBCD enzyme, RecBCDPs, is a trimeric protein complex comprised of RecC, RecB, and RecD subunits. RecBCD enzyme is essential for P. syringae growth at low temperature, and it protects cells from low temperature induced replication arrest. In this study, we show that the RecBCDPs enzyme displays distinct biochemical behaviors. Unlike E. coli RecBCD enzyme, the RecD subunit is indispensable for RecBCDPs function. The RecD motor activity is essential for the Chi-like fragments production in P...
2018: PloS One
https://www.readbyqxmd.com/read/29774234/the-fission-yeast-stn1-ten1-complex-limits-telomerase-activity-via-its-sumo-interacting-motif-and-promotes-telomeres-replication
#6
Samah Matmati, Mélina Vaurs, José M Escandell, Laetitia Maestroni, Toru M Nakamura, Miguel G Ferreira, Vincent Géli, Stéphane Coulon
Mammalian CST (CTC1-STN1-TEN1) complex fulfills numerous functions including rescue of the stalled replication forks and termination of telomerase action. In fission yeast lacking the CTC1 ortholog, the Stn1-Ten1 complex restricts telomerase action via its sumoylation-mediated interaction with Tpz1TPP1 . We identify a small ubiquitin-like modifier (SUMO)-interacting motif (SIM) in the carboxyl-terminal part of Stn1 and show that this domain is crucial for SUMO and Tpz1-SUMO interactions. Point mutations in the SIM (Stn1-226) lead to telomere elongation, impair Stn1-Ten1 recruitment to telomeres, and enhance telomerase binding, revealing that Stn1 SIM domain contributes to the inhibition of telomerase activity at chromosome ends...
May 2018: Science Advances
https://www.readbyqxmd.com/read/29773570/hdna2-nuclease-helicase-promotes-centromeric-dna-replication-and-genome-stability
#7
Zhengke Li, Bochao Liu, Weiwei Jin, Xiwei Wu, Mian Zhou, Vincent Wenzhe Liu, Ajay Goel, Zhiyuan Shen, Li Zheng, Binghui Shen
DNA2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double-strand breaks. Similar such helicase activity for resolving secondary structures and structure-specific nuclease activity are needed during DNA replication to process the chromosome-specific higher order repeat units present in the centromeres of human chromosomes. Here, we show that DNA2 binds preferentially to centromeric DNA The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate DNA replication fork movement...
May 17, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29760651/human-dna-helicase-b-as-a-candidate-for-unwinding-secondary-cgg-repeat-structures-at-the-fragile-x-mental-retardation-gene
#8
Gulfem D Guler, Zev Rosenwaks, Jeannine Gerhardt
The fragile X syndrome (FXS) is caused by a CGG repeat expansion at the fragile X mental retardation ( FMR1 ) gene. FMR1 alleles with more than 200 CGG repeats bear chromosomal fragility when cells experience folate deficiency. CGG repeats were reported to be able to form secondary structures, such as hairpins, in vitro . When such secondary structures are formed, repeats can lead to replication fork stalling even in the absence of any additional perturbation. Indeed, it was recently shown that the replication forks stall at the endogenous FMR1 locus in unaffected and FXS cells, suggesting the formation of secondary repeat structures at the FMR1 gene in vivo ...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29751847/asf1-is-required-to-load-histones-on-the-hira-complex-in-preparation-of-paternal-chromatin-assembly-at-fertilization
#9
Béatrice Horard, Laure Sapey-Triomphe, Emilie Bonnefoy, Benjamin Loppin
BACKGROUND: Anti-Silencing Factor 1 (ASF1) is a conserved H3-H4 histone chaperone involved in both Replication-Coupled and Replication-Independent (RI) nucleosome assembly pathways. At DNA replication forks, ASF1 plays an important role in regulating the supply of H3.1/2 and H4 to the CAF-1 chromatin assembly complex. ASF1 also provides H3.3-H4 dimers to HIRA and DAXX chaperones for RI nucleosome assembly. The early Drosophila embryo is an attractive system to study chromatin assembly in a developmental context...
May 11, 2018: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/29742437/atp-binding-to-rad5-initiates-replication-fork-reversal-by-inducing-the-unwinding-of-the-leading-arm-and-the-formation-of-the-holliday-junction
#10
Soochul Shin, Kwangbeom Hyun, Jaehoon Kim, Sungchul Hohng
Replication fork reversal is one of the major pathways for reactivating stalled DNA replication. Many enzymes with replication fork reversal activity have DNA-unwinding activity as well, but none of the fork reversal enzymes in the SWI/SNF family shows a separate DNA-unwinding activity, raising the question of how they initiate the remodeling process. Here, we found ATP binding to Rad5 induces the unwinding of the leading arm of the replication fork and proximally positions the leading and lagging arms. This facilitates the spontaneous remodeling of the replication fork into a four-way junction...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29741650/flap-endonuclease-overexpression-drives-genome-instability-and-dna-damage-hypersensitivity-in-a-pcna-dependent-manner
#11
Jordan R Becker, David Gallo, Wendy Leung, Taylor Croissant, Yee Mon Thu, Hai Dang Nguyen, Timothy K Starr, Grant W Brown, Anja-Katrin Bielinsky
Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase. This was accompanied by increased phosphorylation of the checkpoint kinase Rad53 and histone H2A-S129...
May 7, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29739811/tel1-atm-prevents-degradation-of-replication-forks-that-reverse-after-topoisomerase-poisoning
#12
Luca Menin, Sebastian Ursich, Camilla Trovesi, Ralph Zellweger, Massimo Lopes, Maria Pia Longhese, Michela Clerici
In both yeast and mammals, the topoisomerase poison camptothecin (CPT) induces fork reversal, which has been proposed to stabilize replication forks, thus providing time for the repair of CPT-induced lesions and supporting replication restart. We show that Tel1, the Saccharomyces cerevisiae orthologue of human ATM kinase, stabilizes CPT-induced reversed forks by counteracting their nucleolytic degradation by the MRX complex. Tel1-lacking cells are hypersensitive to CPT specifically and show less reversed forks in the presence of CPT The lack of Mre11 nuclease activity restores wild-type levels of reversed forks in CPT-treated tel1 Δ cells without affecting fork reversal in wild-type cells...
May 8, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29727617/genome-wide-control-of-heterochromatin-replication-by-the-telomere-capping-protein-trf2
#13
Aaron Mendez-Bermudez, Liudmyla Lototska, Serge Bauwens, Marie-Josèphe Giraud-Panis, Olivier Croce, Karine Jamet, Agurtzane Irizar, Macarena Mowinckel, Stephane Koundrioukoff, Nicolas Nottet, Genevieve Almouzni, Mare-Paule Teulade-Fichou, Michael Schertzer, Mylène Perderiset, Arturo Londoño-Vallejo, Michelle Debatisse, Eric Gilson, Jing Ye
Hard-to-replicate regions of chromosomes (e.g., pericentromeres, centromeres, and telomeres) impede replication fork progression, eventually leading, in the event of replication stress, to chromosome fragility, aging, and cancer. Our knowledge of the mechanisms controlling the stability of these regions is essentially limited to telomeres, where fragility is counteracted by the shelterin proteins. Here we show that the shelterin subunit TRF2 ensures progression of the replication fork through pericentromeric heterochromatin, but not centromeric chromatin...
May 3, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29709199/the-mre11-rad50-nbs1-complex-conducts-the-orchestration-of-damage-signaling-and-outcomes-to-stress-in-dna-replication-and-repair
#14
Aleem Syed, John A Tainer
Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette-ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11-RAD50-NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection...
April 25, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29708067/polymerase-delta-in-eukaryotes-how-is-it-transiently-exchanged-with-specialized-dna-polymerases-during-translesion-dna-synthesis
#15
Fengyu Liu, Yulong Yang, Yajing Zhou
Precise duplication of the human genome is constantly threatened by a variety of genotoxic insults. During S-phase, those damaged template bases could be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles instead of repairing them, allowing replicative machinery to resume beyond the offending lesions. Two distinct strategies of DDT, template switching and translesion DNA synthesis (TLS), are employed in eukaryotes. In the former process, the newly synthesized sister chromatid is utilized as an undamaged template to restart recombination-dependent DNA synthesis in an error-free manner...
April 30, 2018: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/29704518/inhibition-of-mapkapk2-mk2-facilitates-dna-replication-upon-cancer-cell-treatment-with-gemcitabine-but-not-cisplatin
#16
Yizhu Li, Frederik Köpper, Matthias Dobbelstein
The signaling pathway driven by p38 and MAPKAPK2 alias MK2 is activated as part of stress responses, and these kinases represent attractive drug targets for cancer therapy. However, seemingly conflicting results were obtained when assessing the role of MK2 in chemotherapy. MK2 inhibitors were reported to either enhance or diminish the chemosensitivity of cancer cells. Here we show that this strongly depends on the particular chemotherapeutic drug. Two different MK2 inhibitors increased the proliferating fraction of pancreatic cancer-derived cells upon treatment with gemcitabine, whereas no consistent protection against cisplatin was observed...
April 25, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29703825/-samhd1-mutations-disrupt-replication-fork-progression-to-induce-ifn
#17
(no author information available yet)
SAMHD1 activates MRE11 exonuclease activity to prevent release of ssDNA from stalled replication forks.
April 27, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29686321/chromatin-conformation-regulates-the-coordination-between-dna-replication-and-transcription
#18
Ricardo Almeida, José Miguel Fernández-Justel, Cristina Santa-María, Jean-Charles Cadoret, Laura Cano-Aroca, Rodrigo Lombraña, Gonzalo Herranz, Alessandra Agresti, María Gómez
Chromatin is the template for the basic processes of replication and transcription, making the maintenance of chromosomal integrity critical for cell viability. To elucidate how dividing cells respond to alterations in chromatin structure, here we analyse the replication programme of primary cells with altered chromatin configuration caused by the genetic ablation of the HMGB1 gene, or three histone H1 genes. We find that loss of chromatin compaction in H1-depleted cells triggers the accumulation of stalled forks and DNA damage as a consequence of transcription-replication conflicts...
April 23, 2018: Nature Communications
https://www.readbyqxmd.com/read/29686033/homologous-recombination-and-replication-fork-protection-brca2-and-more
#19
Weiran Feng, Maria Jasin
BRCA2 is a breast and ovarian tumor suppressor that guards against genome instability, a hallmark of cancer. Significant progress has been made in improving our understanding of BRCA2 function from biochemical, cellular, and mouse studies. The knowledge gained has been actively exploited to develop therapeutic strategies, including PARP inhibition, which has shown promising clinical outcomes. Recently, tremendous excitement has been generated by the findings of the roles of BRCA2 and other proteins in suppressing replication stress through homologous recombination and in the protection of stalled replication forks...
April 23, 2018: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29674319/long-repeating-ttaggg-n-single-stranded-dna-self-condenses-into-compact-beaded-filaments-stabilized-by-g-quadruplex-formation
#20
Anirban Kar, Nathan Jones, N Özlem Arat, Richard Fishel, Jack Griffith
Conformations adopted by long stretches of single stranded DNA (ssDNA) are of central interest in understanding the architecture of replication forks, R loops, and other structures generated during DNA metabolism in vivo. This is particularly so if the ssDNA consists of short nucleotide repeats. Such studies have been hampered by the lack of defined substrates greater than ~150 nt, and the absence of high-resolution biophysical approaches. Here we describe the generation of very long ssDNA consisting of the mammalian telomeric repeat (5'-TTAGGG-3')n as well as the interrogation of its structure by electron microscopy (EM) and single molecule magnetic tweezers (smMT)...
April 19, 2018: Journal of Biological Chemistry
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