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https://www.readbyqxmd.com/read/27932446/topoisomerase-i-mediated-cleavage-at-unrepaired-ribonucleotides-generates-dna-double-strand-breaks
#1
Shar-Yin N Huang, Jessica S Williams, Mercedes E Arana, Thomas A Kunkel, Yves Pommier
Ribonuclease activity of topoisomerase I (Top1) causes DNA nicks bearing 2',3'-cyclic phosphates at ribonucleotide sites. Here, we provide genetic and biochemical evidence that DNA double-strand breaks (DSBs) can be directly generated by Top1 at sites of genomic ribonucleotides. We show that RNase H2-deficient yeast cells displayed elevated frequency of Rad52 foci, inactivation of RNase H2 and RAD52 led to synthetic lethality, and combined loss of RNase H2 and RAD51 induced slow growth and replication stress...
December 8, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27930670/ku-binding-on-telomeres-occurs-at-sites-distal-from-the-physical-chromosome-ends
#2
Mélanie V Larcher, Emeline Pasquier, R Stephen MacDonald, Raymund J Wellinger
The Ku complex binds non-specifically to DNA breaks and ensures repair via NHEJ. However, Ku is also known to bind directly to telomeric DNA ends and its presence there is associated with telomere capping, but avoiding NHEJ. How the complex discriminates between a DNA break and a telomeric extremity remains unknown. Our results using a tagged Ku complex, or a chromosome end capturing method, in budding yeast show that yKu association with telomeres can occur at sites distant from the physical end, on sub-telomeric elements, as well as on interstitial telomeric repeats...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27918542/the-role-of-break-induced-replication-in-large-scale-expansions-of-cag-n-ctg-n-repeats
#3
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/27911848/global-analysis-of-genomic-instability-caused-by-dna-replication-stress-in-saccharomyces-cerevisiae
#4
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/27908384/dna-replication-after-mutagenic-treatment-in-hordeum-vulgare
#5
Jolanta Kwasniewska, Arita Kus, Monika Swoboda, Agnieszka Braszewska-Zalewska
The temporal and spatial properties of DNA replication in plants related to DNA damage and mutagenesis is poorly understood. Experiments were carried out to explore the relationships between DNA replication, chromatin structure and DNA damage in nuclei from barley root tips. We quantitavely analysed the topological organisation of replication foci using pulse EdU labelling during the S phase and its relationship with the DNA damage induced by mutagenic treatment with maleic hydrazide (MH), nitroso-N-methyl-urea (MNU) and gamma ray...
December 2016: Mutation Research
https://www.readbyqxmd.com/read/27903905/human-mlh1-suppresses-the-insertion-of-telomeric-sequences-at-intra-chromosomal-sites-in-telomerase-expressing-cells
#6
Pingping Jia, Megan Chastain, Ying Zou, Chengtao Her, Weihang Chai
Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27894771/radiation-induced-dna-protein-cross-links-mechanisms-and-biological-significance
#7
Toshiaki Nakano, Xu Xu, Amir M H Salem, Mahmoud I Shoulkamy, Hiroshi Ide
Ionizing radiation produces various DNA lesions such as base damage, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and DNA-protein cross-links (DPCs). Of these, the biological significance of DPCs remains elusive. In this article, we focus on radiation-induced DPCs and review the current understanding of their induction, properties, repair, and biological consequences. When cells are irradiated, the formation of base damage, SSBs, and DSBs are promoted in the presence of oxygen. Conversely, that of DPCs is promoted in the absence of oxygen, suggesting their importance in hypoxic cells, such as those present in tumors...
November 25, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27894682/molecular-mechanisms-by-which-in-vivo-exposure-to-exogenous-chemical-genotoxic-agents-can-lead-to-micronucleus-formation-in-lymphocytes-in-vivo-and-ex-vivo-in-humans
#8
REVIEW
Michael Fenech, Siegfried Knasmueller, Claudia Bolognesi, Stefano Bonassi, Nina Holland, Lucia Migliore, Fabrizio Palitti, Adayapalam T Natarajan, Micheline Kirsch-Volders
The purpose of this review is to summarise current knowledge on the molecular mechanisms by which in vivo exposure to exogenous chemical genotoxins in humans induces micronuclei (MNi) and other nuclear anomalies in lymphocytes in vivo and ex vivo after nuclear division in vitro. MNi originate from acentric chromosome fragments and/or whole chromosomes that are unable to engage with the mitotic spindle and/or fail to segregate properly to the daughter nuclei during anaphase. The lagging fragments or whole chromosomes are surrounded by membrane and become MNi...
October 2016: Mutation Research
https://www.readbyqxmd.com/read/27893960/eukaryotic-dna-polymerases-in-homologous-recombination
#9
Mitch McVey, Varandt Y Khodaverdian, Damon Meyer, Paula Gonçalves Cerqueira, Wolf-Dietrich Heyer
Homologous recombination (HR) is a central process to ensure genomic stability in somatic cells and during meiosis. HR-associated DNA synthesis determines in large part the fidelity of the process. A number of recent studies have demonstrated that DNA synthesis during HR is conservative, less processive, and more mutagenic than replicative DNA synthesis. In this review, we describe mechanistic features of DNA synthesis during different types of HR-mediated DNA repair, including synthesis-dependent strand annealing, break-induced replication, and meiotic recombination...
November 23, 2016: Annual Review of Genetics
https://www.readbyqxmd.com/read/27892797/nek8-regulates-dna-damage-induced-rad51-foci-formation-and-replication-fork-protection
#10
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/27869555/the-influence-of-the-ctip-polymorphism-q418p-on-homologous-recombination-and-predisposition-to-radiation-induced-tumorigenesis-mainly-raml-in-mice
#11
Agata Patel, Jennifer Anderson, Daniela Kraft, Rosemary Finnon, Paul Finnon, Cheryl L Scudamore, Grainne Manning, Robert Bulman, Natalie Brown, Simon Bouffler, Peter O'Neill, Christophe Badie
Exposure to ionizing radiation increases the incidence of acute myeloid leukemia (AML), which has been diagnosed in Japanese atomic bombing survivors, as well as patients treated with radiotherapy. The genetic basis for susceptibility to radiation-induced AML is not well characterized. We previously identified a candidate murine gene for susceptibility to radiation-induced AML (rAML): C-terminal binding protein (CTBP)-interacting protein (CTIP)/retinoblastoma binding protein 8 (RBBP8). This gene is essential for embryonic development, double-strand break (DSB) resection in homologous recombination (HR) and tumor suppression...
November 21, 2016: Radiation Research
https://www.readbyqxmd.com/read/27852524/targeting-dna-flap-endonuclease-1-to-impede-breast-cancer-progression
#12
Lingfeng He, Yilan Zhang, Hongfang Sun, Feng Jiang, Huan Yang, Huan Wu, Ting Zhou, Sencai Hu, Chandra Sekhar Kathera, Xiaojun Wang, Haoyan Chen, Hongzhi Li, Binghui Shen, Yongqiang Zhu, Zhigang Guo
DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells...
November 10, 2016: EBioMedicine
https://www.readbyqxmd.com/read/27849610/dna-polymerase-%C3%AE-limits-chromosomal-damage-and-promotes-cell-survival-following-aflatoxin-exposure
#13
Ying-Chih Lin, Nichole Owen, Irina G Minko, Sabine S Lange, Liang Li, Michael P Stone, Richard D Wood, Amanda K McCullough, R Stephen Lloyd
Routine dietary consumption of foods that contain aflatoxins is the second leading cause of environmental carcinogenesis worldwide. Aflatoxin-driven mutagenesis is initiated through metabolic activation of aflatoxin B1 (AFB1) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB1-N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening yielding formamidopyrimidine AFB1 (AFB1-Fapy-dG). Because this latter adduct is known to persist in human tissues and contributes to the high frequency G-to-T mutation signature associated with many hepatocellular carcinomas, we sought to establish the identity of the polymerase(s) involved in processing this lesion...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27832076/complex-breakpoints-and-template-switching-associated-with-non-canonical-termination-of-homologous-recombination-in-mammalian-cells
#14
Andrea J Hartlerode, Nicholas A Willis, Anbazhagan Rajendran, John P Manis, Ralph Scully
A proportion of homologous recombination (HR) events in mammalian cells resolve by "long tract" gene conversion, reflecting copying of several kilobases from the donor sister chromatid prior to termination. Cells lacking the major hereditary breast/ovarian cancer predisposition genes, BRCA1 or BRCA2, or certain other HR-defective cells, reveal a bias in favor of long tract gene conversion, suggesting that this aberrant HR outcome might be connected with genomic instability. If termination of gene conversion occurs in regions lacking homology with the second end of the break, the normal mechanism of HR termination by annealing (i...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27806303/hydroxyurea-mediated-cytotoxicity-without-inhibition-of-ribonucleotide-reductase
#15
Li Phing Liew, Zun Yi Lim, Matan Cohen, Ziqing Kong, Lisette Marjavaara, Andrei Chabes, Stephen D Bell
In many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27797382/defective-replication-stress-response-inhibits-lymphomagenesis-and-impairs-lymphocyte-reconstitution
#16
M V Puccetti, M A Fischer, M P Arrate, K L Boyd, R J Duszynski, R Bétous, D Cortez, C M Eischen
DNA replication stress promotes genome instability in cancer. However, the contribution of the replication stress response to the development of malignancies remains unresolved. The DNA replication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replication fork collapse, a cause of DNA breaks and apoptosis. While the fork regression/remodeling functions of SMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear. Using a gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed a significant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1...
October 31, 2016: Oncogene
https://www.readbyqxmd.com/read/27775089/cell-resistance-to-the-cytolethal-distending-toxin-involves-an-association-of-dna-repair-mechanisms
#17
Elisabeth Bezine, Yann Malaisé, Aurore Loeuillet, Marianne Chevalier, Elisa Boutet-Robinet, Bernard Salles, Gladys Mirey, Julien Vignard
The Cytolethal Distending Toxin (CDT), produced by many bacteria, has been associated with various diseases including cancer. CDT induces DNA double-strand breaks (DSBs), leading to cell death or mutagenesis if misrepaired. At low doses of CDT, other DNA lesions precede replication-dependent DSB formation, implying that non-DSB repair mechanisms may contribute to CDT cell resistance. To address this question, we developed a proliferation assay using human cell lines specifically depleted in each of the main DNA repair pathways...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27773933/targeting-transcription-coupled-nucleotide-excision-repair-overcomes-resistance-in-chronic-lymphocytic-leukemia
#18
G Lohmann, E Vasyutina, J Bloehdorn, N Reinart, J I Schneider, V Babu, G Knittel, G Crispatzu, P Mayer, C Prinz, J K Muenzner, B Biersack, D G Efremov, L Chessa, C D Herling, S Stilgenbauer, M Hallek, R Schobert, H C Reinhardt, B Schumacher, M Herling
Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27773744/fhit-and-wwox-loss-associated-genome-instability-a-genome-caretaker-one-two-punch
#19
Morgan S Schrock, Jenna R Karras, Matthew J Guggenbiller, Teresa Druck, Bahadir Batar, Kay Huebner
Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs...
September 26, 2016: Advances in Biological Regulation
https://www.readbyqxmd.com/read/27760777/alternative-lengthening-of-human-telomeres-is-a-conservative-dna-replication-process-with-features-of-break-induced-replication
#20
Fani-Marlen Roumelioti, Sotirios K Sotiriou, Vasiliki Katsini, Maria Chiourea, Thanos D Halazonetis, Sarantis Gagos
Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells...
December 2016: EMBO Reports
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