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https://www.readbyqxmd.com/read/28087741/14-3-3sigma-contributes-to-radioresistance-by-regulating-dna-repair-and-cell-cycle-via-parp1-and-chk2
#1
Yifan Chen, Zhaomin Li, Zizheng Dong, Jenny Beebe, Ke Yang, Liwu Fu, Jian-Ting Zhang
: 14-3-3sigma has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3sigma contributes to these resistances via inhibiting apoptosis and arresting cells in G2/M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3sigma causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2/M phase following DNA-damaging treatments...
January 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28087249/nick-initiated-homologous-recombination-protecting-the-genome-one-strand-at-a-time
#2
REVIEW
Lianne E M Vriend, Przemek M Krawczyk
Homologous recombination (HR) is an essential, widely conserved mechanism that utilizes a template for accurate repair of DNA breaks. Some early HR models, developed over five decades ago, anticipated single-strand breaks (nicks) as initiating lesions. Subsequent studies favored a more double-strand break (DSB)-centered view of HR initiation and at present this pathway is primarily considered to be associated with DSB repair. However, mounting evidence suggests that nicks can indeed initiate HR directly, without first being converted to DSBs...
December 29, 2016: DNA Repair
https://www.readbyqxmd.com/read/28081176/radiation-induced-apoptosis-of-murine-bone-marrow-cells-is-independent-of-early-growth-response-1-egr1
#3
Karine Z Oben, Beth W Gachuki, Sara S Alhakeem, Mary K McKenna, Ying Liang, Daret K St Clair, Vivek M Rangnekar, Subbarao Bondada
An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis-p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise...
2017: PloS One
https://www.readbyqxmd.com/read/28081154/sensitization-of-radioresistant-prostate-cancer-cells-by-resveratrol-isolated-from-arachis-hypogaea-stems
#4
Yu-An Chen, Hsiu-Man Lien, Min-Chuan Kao, U-Ging Lo, Li-Chiung Lin, Chun-Jung Lin, Sheau-Jiun Chang, Chia-Chang Chen, Jer-Tsong Hsieh, Ho Lin, Chih-Hsin Tang, Chih-Ho Lai
Resveratrol (RV, 3,4',5-trihydroxystilbene) is naturally produced by a wide variety of plants including grapes and peanuts (Arachis hypogaea). However, the yield of RV from peanut stem and its potential radiosensitizing effects in prostate cancer (PCa) have not been well investigated. In this study, we characterized RV in peanut stem extract (PSE) for the first time and showed that both RV and PSE dose-dependently induced cell death in DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells with the radioresistant phenotype...
2017: PloS One
https://www.readbyqxmd.com/read/28079299/a-platinum-blue-complex-exerts-its-cytotoxic-activity-via-dna-damage-and-induces-apoptosis-in-cancer-cells
#5
Zelal Adiguzel, Seniz Ozalp-Yaman, Gokalp Celik, Safia Salem, Tugba Bagci-Onder, Filiz Senbabaoglu, Yüksel Cetin, Ceyda Acilan
Here, we describe the characteristics of a Pt-blue complex [Pt4 (2-atp)8 (H2 O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single and double stranded breaks (DBS) on DNA in vitro, but no DSBs in cells...
January 12, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28079255/moonlighting-at-replication-forks-a-new-life-for-homologous-recombination-proteins-brca1-brca2-and-rad51
#6
REVIEW
Arun Mouli Kolinjivadi, Vincenzo Sannino, Anna de Antoni, Hervé Técher, Giorgio Baldi, Vincenzo Costanzo
Coordination between DNA replication and DNA repair ensures maintenance of genome integrity, which is lost in cancer cells. Emerging evidence has linked Homologous Recombination (HR) proteins RAD51, BRCA1 and BRCA2 to the stability of nascent DNA. This function appears to be distinct from Double Strand Break (DSB) repair and is in part due to the prevention of MRE11-mediated degradation of nascent DNA at stalled forks. The role of RAD51 in fork protection resembles the activity described for its prokaryotic ortholog RecA, which prevents nuclease-mediated degradation of DNA and promotes replication fork restart in cells challenged by DNA damaging agents...
January 12, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28077781/effects-of-an-unusual-poison-identify-a-lifespan-role-for-topoisomerase-2-in-saccharomyces-cerevisiae
#7
Gregory Tombline, Jonathan I Millen, Bogdan Polevoda, Matan Rapaport, Bonnie Baxter, Michael Van Meter, Matthew Gilbertson, Joe Madrey, Gary A Piazza, Lynn Rasmussen, Krister Wennerberg, E Lucile White, John L Nitiss, David S Goldfarb
A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability...
January 5, 2017: Aging
https://www.readbyqxmd.com/read/28077446/regulating-chromosomal-movement-by-the-cochaperone-fkb-6-ensures-timely-pairing-and-synapsis
#8
Benjamin Alleva, Nathan Balukoff, Amy Peiper, Sarit Smolikove
In meiotic prophase I, homologous chromosome pairing is promoted through chromosome movement mediated by nuclear envelope proteins, microtubules, and dynein. After proper homologue pairing has been established, the synaptonemal complex (SC) assembles along the paired homologues, stabilizing their interaction and allowing for crossing over to occur. Previous studies have shown that perturbing chromosome movement leads to pairing defects and SC polycomplex formation. We show that FKB-6 plays a role in SC assembly and is required for timely pairing and proper double-strand break repair kinetics...
January 11, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28076794/brca1-directs-the-repair-pathway-to-homologous-recombination-by-promoting-53bp1-dephosphorylation
#9
Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin-Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata
BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076779/transcription-dynamics-prevent-rna-mediated-genomic-instability-through-srpk2-dependent-ddx23-phosphorylation
#10
Sreerama Chaitanya Sridhara, Sílvia Carvalho, Ana Rita Grosso, Lina Marcela Gallego-Paez, Maria Carmo-Fonseca, Sérgio Fernandes de Almeida
Genomic instability is frequently caused by nucleic acid structures termed R-loops that are formed during transcription. Despite their harmful potential, mechanisms that sense, signal, and suppress these structures remain elusive. Here, we report that oscillations in transcription dynamics are a major sensor of R-loops. We show that pausing of RNA polymerase II (RNA Pol II) initiates a signaling cascade whereby the serine/arginine protein kinase 2 (SRPK2) phosphorylates the DDX23 helicase, culminating in the suppression of R-loops...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076755/rad51-is-a-selective-dna-repair-target-to-radiosensitize-glioma-stem-cells
#11
Harry O King, Tim Brend, Helen L Payne, Alexander Wright, Thomas A Ward, Karan Patel, Teklu Egnuni, Lucy F Stead, Anjana Patel, Heiko Wurdak, Susan C Short
Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation...
January 10, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28075014/knockdown-of-rev3-synergizes-with-atr-inhibition-to-promote-apoptosis-induced-by-cisplatin-in-lung-cancer-cells
#12
He-Guo Jiang, Ping Chen, Jin-Yu Su, Ming Wu, Hai Qian, Yi Wang, Jian Li
It has been demonstrated that REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase ζ, play an important role in DNA damage response (DDR) induced by cisplatin, and Ataxia telangietasia mutated and Rad-3-related (ATR) knase is a central player in activating cell cycle checkpoint, stabilizing replication forks, regulating DDR, and promoting repair of DNA damage caused by cisplatin. Cancer cells deficient in either one of REV3 and ATR are more sensitive to cisplatin. However, whether co-inhibition of REV3 and ATR can further increase sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin is not clear...
January 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28073364/lack-of-mre11-rad50-nbs1-mrn-complex-detection-occurs-frequently-in-low-grade-epithelial-ovarian-cancer
#13
Simone Brandt, Eleftherios P Samartzis, Anne-Katrin Zimmermann, Daniel Fink, Holger Moch, Aurelia Noske, Konstantin J Dedes
BACKGROUND: BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC)...
January 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28069724/synthetic-lethality-exploitation-by-an-anti-trop-2-sn-38-antibody-drug-conjugate-immu-132-plus-parp-inhibitors-in-brca1-2-wild-type-triple-negative-breast-cancer
#14
Thomas M Cardillo, Robert M Sharkey, Diane L Rossi, Roberto Arrojo, Ali Mostafa, David M Goldenberg
PURPOSE: Both Poly(ADP-ribose) polymerase inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC. EXPERIMENTAL DESIGN: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28069693/dna-fragile-site-breakage-as-a-measure-of-chemical-exposure-and-predictor-of-individual-susceptibility-to-form-oncogenic-rearrangements
#15
Christine E Lehman, Laura W Dillon, Yuri E Nikiforov, Yuh-Hwa Wang
Chromosomal rearrangements induced by non-radiation causes contribute to the majority of oncogenic fusions found in cancer. Treatment of human thyroid cells with fragile site-inducing laboratory chemicals can cause preferential DNA breakage at the RET gene and generate the RET/PTC1 rearrangement, a common driver mutation in papillary thyroid carcinomas (PTC). Here, we demonstrate that treatment with non-cytotoxic levels of environmental chemicals (benzene and diethylnitrosamine) or chemotherapeutic agents (etoposide and doxorubicin) generates significant DNA breakage within RET at levels similar to those generated by fragile site-inducing laboratory chemicals...
January 9, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28068556/organizing-dna-repair-in-the-nucleus-dsbs-hit-the-road
#16
REVIEW
Aline Marnef, Gaëlle Legube
In the past decade, large-scale movements of DNA double strand breaks (DSBs) have repeatedly been identified following DNA damage. These mobility events include clustering, anchoring or peripheral movement at subnuclear structures. Recent work suggests roles for motion in homology search and in break sequestration to preclude deleterious outcomes. Yet, the precise functions of these movements still remain relatively obscure, and the same holds true for the determinants. Here we review recent advances in this exciting area of research, and highlight that a recurrent characteristic of mobile DSBs may lie in their inability to undergo rapid repair...
January 6, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28068427/s1-type-endonuclease-2-in-dedifferentiating-arabidopsis-protoplasts-translocation-to-the-nucleus-in-senescing-protoplasts-is-associated-with-de-glycosylation
#17
Yemima Givaty-Rapp, Narendra Singh Yadav, Asif Khan, Gideon Grafi
Cell dedifferentiation characterizes the transition of leaf cells to protoplasts and is accompanied by global chromatin decondensation. Here we show that in Arabidopsis, chromocentric chromatin undergoes prompt and gradual decondensation upon protoplasting. We hypothesized that prompt chromatin decondensation is unlikely to be driven solely by epigenetic means and other factors might be involved. We investigated the possibility that S1-type endonucleases are involved in prompt chromatin decondensation via their capability to target and cleave unpaired regions within superhelical DNA, leading to chromatin relaxation...
2017: PloS One
https://www.readbyqxmd.com/read/28067485/honokiol-inhibits-dna-polymerases-%C3%AE-and-%C3%AE-and-increases-bleomycin-sensitivity-of-human-cancer-cells
#18
Prakasha Gowda, Zucai Suo, Thomas E Spratt
A major concept to sensitize cancer cells to DNA damaging agents is by inhibiting proteins in the DNA repair pathways. X-Family DNA polymerases play critical roles in both base excision repair (BER) and non-homologous end joining (NHEJ). In this study, we examined the effectiveness of honokiol to inhibit human DNA polymerase β (pol β), which is involved in BER, and DNA polymerase λ (pol λ), which is involved in NHEJ. Kinetic analysis with purified showed that honokiol inhibited DNA polymerase activity. The inhibition mode for the polymerases was a mixed-function noncompetitive inhibition with respect to the substrate, dCTP...
January 9, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28067217/characterization-of-the-interplay-between-dna-repair-and-crispr-cas9-induced-dna-lesions-at-an-endogenous-locus
#19
Anne Bothmer, Tanushree Phadke, Luis A Barrera, Carrie M Margulies, Christina S Lee, Frank Buquicchio, Sean Moss, Hayat S Abdulkerim, William Selleck, Hariharan Jayaram, Vic E Myer, Cecilia Cotta-Ramusino
The CRISPR-Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28065739/r-loop-depletion-by-over-expressed-rnase-h1-in-mouse-b-cells-increases-activation-induced-deaminase-access-to-the-transcribed-strand-without-altering-frequency-of-isotype-switching
#20
Robert W Maul, Hyongi Chon, Kiran Sakhuja, Susana M Cerritelli, Lina A Gugliotti, Patricia J Gearhart, Robert J Crouch
R-loops, three-strand structures consisting of mRNA hybridized to the complementary DNA and a single-stranded DNA loop, are formed in switch regions on the heavy-chain immunoglobulin locus. To determine if R-loops have a direct effect on any of the steps involved in isotype switching, we generated a transgenic mouse that over-expressed RNase H1, an enzyme that cleaves the RNA of RNA/DNA hybrids in B cells. R-loops in the switch μ region were depleted by 70% in ex vivo activated splenic B cells. Frequencies of isotype switching to IgG1, IgG2b, IgG2c, and IgG3 were the same as C57BL/6 control cells...
January 6, 2017: Journal of Molecular Biology
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