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Parp1 dna

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https://www.readbyqxmd.com/read/29750868/brca-status-does-not-predict-synergism-of-a-carboplatin-and-olaparib-combination-in-high-grade-serous-ovarian-cancer-cell-lines
#1
Yen Ting Shen, James C Evans, Gaetano Zafarana, Christine Allen, Micheline Piquette-Miller
Over 50% of epithelial ovarian cancers express the BRCAness profile that leads to a dysfunctional homologous recombination repair system. The combination of a dysfunctional homologous recombination repair system and a poly (ADP-ribose) polymerase (PARP) inhibitor results in a synthetic lethal phenotype. The PARP inhibitor olaparib, approved as a monotherapy for patients with a germline BRCA mutation, has shown promising results in preclinical studies when combined with DNA damaging agents such as carboplatin...
May 11, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29748565/genome-wide-and-high-density-crispr-cas9-screens-identify-point-mutations-in-parp1-causing-parp-inhibitor-resistance
#2
Stephen J Pettitt, Dragomir B Krastev, Inger Brandsma, Amy Dréan, Feifei Song, Radoslav Aleksandrov, Maria I Harrell, Malini Menon, Rachel Brough, James Campbell, Jessica Frankum, Michael Ranes, Helen N Pemberton, Rumana Rafiq, Kerry Fenwick, Amanda Swain, Sebastian Guettler, Jung-Min Lee, Elizabeth M Swisher, Stoyno Stoynov, Kosuke Yusa, Alan Ashworth, Christopher J Lord
Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 "tag-mutate-enrich" mutagenesis screens, we identify close to full-length mutant forms of PARP1 that cause in vitro and in vivo PARPi resistance. Mutations both within and outside of the PARP1 DNA-binding zinc-finger domains cause PARPi resistance and alter PARP1 trapping, as does a PARP1 mutation found in a clinical case of PARPi resistance...
May 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29747595/the-search-for-a-melanoma-tailored-chemotherapy-in-the-new-era-of-personalized-therapy-a-phase-ii-study-of-chemo-modulating-temozolomide-followed-by-fotemustine-and-a-cooperative-study-of-goim-gruppo-oncologico-italia-meridionale
#3
Michele Guida, Stefania Tommasi, Sabino Strippoli, Maria Iole Natalicchio, Simona De Summa, Rosamaria Pinto, Antonio Cramarossa, Anna Albano, Salvatore Pisconti, Michele Aieta, Ruggiero Ridolfi, Amalia Azzariti, Gabriella Guida, Vito Lorusso, Giusepe Colucci
BACKGROUND: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT)...
May 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29746213/gene-expression-in-parp1-deficient-mice-exposed-to-a-median-lethal-dose-of-gamma-rays
#4
M A Suresh Kumar, Evagelia C Laiakis, Shanaz A Ghandhi, Shad R Morton, Albert J Fornace, Sally A Amundson
There is a current interest in the development of biodosimetric methods for rapidly assessing radiation exposure in the wake of a large-scale radiological event. This work was initially focused on determining the exposure dose to an individual using biological indicators. Gene expression signatures show promise for biodosimetric application, but little is known about how these signatures might translate for the assessment of radiological injury in radiosensitive individuals, who comprise a significant proportion of the general population, and who would likely require treatment after exposure to lower doses...
May 10, 2018: Radiation Research
https://www.readbyqxmd.com/read/29742442/rna-dna-hybrid-interactome-identifies-dxh9-as-a-molecular-player-in-transcriptional-termination-and-r-loop-associated-dna-damage
#5
Agnese Cristini, Matthias Groh, Maiken S Kristiansen, Natalia Gromak
R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA. They play important biological roles and are implicated in pathology. Even so, proteins recognizing these structures are largely undefined. Using affinity purification with the S9.6 antibody coupled to mass spectrometry, we defined the RNA/DNA hybrid interactome in HeLa cells. This consists of known R-loop-associated factors SRSF1, FACT, and Top1, and yet uncharacterized interactors, including helicases, RNA processing, DNA repair, and chromatin factors...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29733391/chd3-and-chd4-recruitment-and-chromatin-remodeling-activity-at-dna-breaks-is-promoted-by-early-poly-adp-ribose-dependent-chromatin-relaxation
#6
Rebecca Smith, Hafida Sellou, Catherine Chapuis, Sébastien Huet, Gyula Timinszky
One of the first events to occur upon DNA damage is the local opening of the compact chromatin architecture, facilitating access of repair proteins to DNA lesions. This early relaxation is triggered by poly(ADP-ribosyl)ation by PARP1 in addition to ATP-dependent chromatin remodeling. CHD4 recruits to DNA breaks in a PAR-dependent manner, although it lacks any recognizable PAR-binding domain, and has the ability to relax chromatin structure. However, its role in chromatin relaxation at the site of DNA damage has not been explored...
May 4, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29712969/nucleolar-nucleoplasmic-shuttling-of-targ1-and-its-control-by-dna-damage-induced-poly-adp-ribosylation-and-by-nucleolar-transcription
#7
Mareike Bütepage, Christian Preisinger, Alexander von Kriegsheim, Anja Scheufen, Eva Lausberg, Jinyu Li, Ferdinand Kappes, Regina Feederle, Sabrina Ernst, Laura Eckei, Sarah Krieg, Gerhard Müller-Newen, Giulia Rossetti, Karla L H Feijs, Patricia Verheugd, Bernhard Lüscher
Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors...
April 30, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29712779/dopamine-triggers-ctcf-dependent-morphological-and-genomic-remodeling-of-astrocytes
#8
Ashley Galloway, Adewale Adeluyi, Bernadette O'Donovan, Miranda L Fisher, Chintada Nageswara Rao, Peyton Critchfield, Mathew Sajish, Jill R Turner, Pavel I Ortinski
Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well-established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation, but instead, relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied by reduced duration and increased frequency of astrocytic Ca2+ transients, but little effect on astrocytic voltage-gated potassium channel currents...
April 30, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29702521/dna-damage-pathways-and-b-cell-lymphomagenesis
#9
Gero Knittel, Tim Rehkämper, Pascal Nieper, Anna Schmitt, Ruth Flümann, H Christian Reinhardt
PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity...
April 26, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29699892/primary-mutational-landscape-linked-with-pre-docetaxel-lactate-dehydrogenase-levels-predicts-docetaxel-response-in-metastatic-castrate-resistant-prostate-cancer
#10
Kenneth Hiew, Claire A Hart, Adnan Ali, Tony Elliott, Vijay Ramani, Vijay Sangar, Maurice Lau, Satish Maddineni, Mick Brown, Noel Clarke
BACKGROUND: Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40-50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. OBJECTIVE: To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. DESIGN, SETTING, AND PARTICIPANTS: Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n=150) and test (n=120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed...
April 23, 2018: European Urology Focus
https://www.readbyqxmd.com/read/29684820/increased-oxidative-stress-mediates-the-antitumor-effect-of-parp-inhibition-in-ovarian-cancer
#11
Dong Hou, Zhaojian Liu, Xiuhua Xu, Qiao Liu, Xiyu Zhang, Beihua Kong, Jian-Jun Wei, Yaoqin Gong, Changshun Shao
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells...
March 30, 2018: Redox Biology
https://www.readbyqxmd.com/read/29681762/correlation-of-high-risk-soft-tissue-sarcoma-biomarker-expression-patterns-with-outcome-following-neoadjuvant-chemoradiation
#12
John M Kane, Anthony Magliocco, Qiang Zhang, Dian Wang, Alex Klimowicz, Jonathan Harris, Jeff Simko, Thomas DeLaney, William Kraybill, David G Kirsch
Background: Sarcoma mortality remains high despite adjuvant chemotherapy. Biomarker predictors of treatment response and outcome could improve treatment selection. Methods: Tissue microarrays (TMAs) were created using pre- and posttreatment tumor from two prospective trials (MGH pilot and RTOG 9514) of neoadjuvant/adjuvant MAID chemotherapy and preoperative radiation. Biomarkers were measured using automated computerized imaging (AQUA or ACIS). Expression was correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS)...
2018: Sarcoma
https://www.readbyqxmd.com/read/29676938/the-development-of-a-biotinylated-nad-applied-human-poly-adp-ribose-polymerase-3-parp3-enzymatic-assay
#13
Ming Ji, Liyuan Wang, Nina Xue, Fangfang Lai, Sen Zhang, Jing Jin, Xiaoguang Chen
Poly(ADP-ribose) polymerase 3 (PARP3) is an important member of the PARP family and shares high structural similarities with both PARP1 and PARP2. The biological roles of PARP3 are currently under investigation; however, several key reports indicate the integral roles of PARP3 in DNA damage repair, and thus it has been investigated as a novel target in oncology. It is clear that the identification of selective PARP3 inhibitors would further advance the understanding of the biological roles of PARP3. Herein, we describe a modified PARP3 screening assay using biotinylated NAD+ as the specialized substrate...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29670134/detection-of-functional-protein-domains-by-unbiased-genome-wide-forward-genetic-screening
#14
Mareike Herzog, Fabio Puddu, Julia Coates, Nicola Geisler, Josep V Forment, Stephen P Jackson
Establishing genetic and chemo-genetic interactions has played key roles in elucidating mechanisms by which certain chemicals perturb cellular functions. In contrast to gene disruption/depletion strategies to identify mechanisms of drug resistance, searching for point-mutational genetic suppressors that can identify separation- or gain-of-function mutations has been limited. Here, by demonstrating its utility in identifying chemical-genetic suppressors of sensitivity to the DNA topoisomerase I poison camptothecin or the poly(ADP-ribose) polymerase inhibitor olaparib, we detail an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast or haploid mammalian cells in a short timeframe, and with potential applications in other haploid systems...
April 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29668892/sumoylation-of-xrcc1-activated-by-poly-adp-ribosyl-ation-regulates-dna-repair
#15
Ling-Yueh Hu, Che-Chang Chang, Yen-Sung Huang, Wen-Cheng Chou, Ying-Mei Lin, Chun-Chen Ho, Wei-Ting Chen, Hsiu-Ming Shih, Chia-Ni Hsiung, Pei-Ei Wu, Chen-Yang Shen
XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation...
April 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29661921/parp1-promotes-the-human-heat-shock-response-by-facilitating-hsf1-binding-to-dna
#16
Mitsuaki Fujimoto, Ryosuke Takii, Arpit Katiyar, Pratibha Srivastava, Akira Nakai
The heat shock response (HSR) is characterized by the rapid and robust induction of heat shock proteins (HSPs), including HSP70, in response to heat shock, and is regulated by heat shock transcription factor 1 (HSF1) in mammalian cells. Poly(ADP-ribose) polymerase 1 (PARP1), which can form a complex with HSF1 through the scaffold protein PARP13, has been suggested to be involved in the HSR. However, its effects on and regulatory mechanisms of the HSR are not well understood. Here, we show that prior to heat shock the HSF1-PARP13-PARP1 complex binds to HSP70 promoter...
April 16, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29653124/doxorubicin-triggers-bioenergetic-failure-and-p53-activation-in-mouse-stem-cell-derived-cardiomyocytes
#17
Teresa Cunha-Oliveira, Luciana L Ferreira, Ana Raquel Coelho, Cláudia M Deus, Paulo J Oliveira
Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor...
April 10, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29627626/the-establishment-of-the-methods-for-free-par-generation-and-par-reader-detection
#18
Yueshuang Ke, Ke Wang, Hui Xu, Chenxin Wang, Jing Zhang, Xianlu Zeng, Ruoxi Wang, Istvan Boldogh, Xueqing Ba
Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor that catalyzes the poly (ADP-ribose) (PAR) onto a variety of target proteins, such as histones, DSB repair factors and PARP1 itself under consumption of NAD+ . Besides, PARP1 can affect a variety of proteins in noncovalent modification manner to carry out specific cellular functions. Here, we establishment a method to generate non-radiolabeled free PAR by PARG moderately cleaving PAR from autoPARylated PARP1, and utilize dot-blot assay to determine the interaction between free PAR and interested proteins...
April 5, 2018: Molecular and Cellular Probes
https://www.readbyqxmd.com/read/29617666/systematic-analysis-of-splice-site-creating-mutations-in-cancer
#19
Reyka G Jayasinghe, Song Cao, Qingsong Gao, Michael C Wendl, Nam Sy Vo, Sheila M Reynolds, Yanyan Zhao, Héctor Climente-González, Shengjie Chai, Fang Wang, Rajees Varghese, Mo Huang, Wen-Wei Liang, Matthew A Wyczalkowski, Sohini Sengupta, Zhi Li, Samuel H Payne, David Fenyö, Jeffrey H Miner, Matthew J Walter, Benjamin Vincent, Eduardo Eyras, Ken Chen, Ilya Shmulevich, Feng Chen, Li Ding
For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29615218/placental-promoter-methylation-of-dna-repair-genes-and-prenatal-exposure-to-particulate-air-pollution-an-environage-cohort-study
#20
Kristof Y Neven, Nelly D Saenen, Letitzia Tarantini, Bram G Janssen, Wouter Lefebvre, Charlotte Vanpoucke, Valentina Bollati, Tim S Nawrot
BACKGROUND: Exposure to particulate air pollution has been linked with risk of carcinogenesis. Damage to repair pathways might have long-term adverse health effects. We aimed to investigate the association of prenatal exposure to air pollution with placental mutation rate and the DNA methylation of key placental DNA repair genes. METHODS: This cohort study used data from the ongoing ENVironmental Influence ON early AGEing (ENVIRONAGE) birth cohort, which enrols pairs of mothers and neonates (singleton births only) at the East-Limburg Hospital (Genk, Belgium)...
April 2018: Lancet. Planetary Health
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