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Synthetic lethality

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https://www.readbyqxmd.com/read/28815832/targeting-the-genome-stability-hub-ctf4-by-stapled-peptide-design
#1
Yuteng Wu, Fabrizio Villa, Joseph Maman, Lina Dobnikar, Yu H Lau, Aline C Simon, Karim Labib, David R Spring, Luca Pellegrini
Exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub that links DNA replication, repair and chromosome segregation, represents a novel target for the synthetic lethality approach. Here we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. Screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, sub-micromolar binding to Ctf4...
August 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28801308/egfr-mutations-compromise-hypoxia-associated-radiation-resistance-through-impaired-replication-fork-associated-dna-damage-repair
#2
Mohammad Saki, Haruhiko Makino, Prashanthi Javvadi, Nozomi Tomimatsu, Lianghao Ding, Jennifer E Clark, Elaine Gavin, Kenichi Takeda, Joel Andrews, Debabrata Saha, Michael D Story, Sandeep Burma, Chaitanya Nirodi
Epidermal growth factor receptor (EGFR) signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non-small cell lung carcinomas (NSCLC) with activating L858R or ΔE746-E750 EGFR mutations exhibit elevated EGFR activity and downstream signaling. Here, relative to wild type (WT) EGFR, mutant (MT) EGFR expression significantly increases radiosensitivity in hypoxic cells. Gene expression profiling in human bronchial epithelial cells (HBEC) revealed that MT-EGFR expression elevated transcripts related to cell cycle and replication in aerobic and hypoxic conditions and down-regulated RAD50, a critical component of non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways...
August 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28800752/a-type-i-combi-targeting-approach-for-the-design-of-molecules-with-enhanced-potency-against-brca1-2-mutant-and-o6-methylguanine-dna-methyltransferase-mgmt-expressing-tumour-cells
#3
Zhor Senhaji Mouhri, Elliot Goodfellow, Bertrand Jean-Claude
BACKGROUND: Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported. In order to improve their efficacy, trials are ongoing to explore their combinations with temozolomide (TMZ)...
August 11, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28790064/atm-deficiency-generating-genomic-instability-sensitizes-pancreatic-ductal-adenocarcinoma-cells-to-therapy-induced-dna-damage
#4
Lukas Perkhofer, Anna Schmitt, Maria Carolina Romero Carrasco, Michaela Ihle, Stephanie Hampp, Dietrich Alexander Ruess, Elisabeth Hessmann, Ronan Russell, André Lechel, Ninel Azoitei, Qiong Lin, Stefan Liebau, Meike Hohwieler, Hanibal Bohnenberger, Marina Lesina, Hana Algül, Laura Gieldon, Evelin Schröck, Jochen Gaedcke, Martin Wagner, Lisa Wiesmüller, Bence Sipos, Thomas Seufferlein, Hans Christian Reinhardt, Pierre-Olivier Frappart, Alexander Kleger
Pancreatic adenocarcinomas (PDAC) harbour recurrent functional mutations of the master DNA damage response kinase ATM which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints, reminiscent of human PDAC...
August 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/28759779/synthetic-lethality-between-murine-dna-repair-factors-xlf-and-dna-pkcs-is-rescued-by-inactivation-of-ku70
#5
Mengtan Xing, Magnar Bjørås, Jeremy A Daniel, Frederick W Alt, Valentyn Oksenych
DNA double-strand breaks (DSBs) are recognized and repaired by the Classical Non-Homologous End-Joining (C-NHEJ) and Homologous Recombination pathways. C-NHEJ includes the core Ku70 and Ku80 (or Ku86) heterodimer that binds DSBs and thus promotes recruitment of accessory downstream NHEJ factors XLF, PAXX, DNA-PKcs, Artemis and other core subunits, XRCC4 and DNA Ligase 4 (Lig4). In the absence of core C-NHEJ factors, DNA repair can be performed by Alternative End-Joining, which likely depends on DNA Ligase 1 and DNA Ligase 3...
July 26, 2017: DNA Repair
https://www.readbyqxmd.com/read/28759753/inhibition-of-rad51-sensitizes-breast-cancer-cells-with-wild-type-pten-to-olaparib
#6
Qian Zhao, Jiawei Guan, Zhiwei Zhang, Jian Lv, Yulu Wang, Likun Liu, Qi Zhou, Weifeng Mao
PTEN is a tumor suppressor gene well characterized as a phosphatase. However, more evidences demonstrate PTEN functions in DNA repair independent of its phosphatase activity, which affects the efficacy of DNA damage anti-tumoral drugs in treating cancer cells with PTEN variations. Using BT549 breast cancer cells, we studied the roles of PTEN in DNA repair and in sensitization of breast cancer cells to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor. Comet assay showed PTEN promoted DNA repair. PTEN-deficient BT549 cells are sensitive to olaparib, which shows the synthetic lethality between PTEN and PARP1...
July 28, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28758914/in-vitro-evaluation-of-sub-lethal-concentrations-of-plant-derived-antifungal-compounds-on-fusaria-growth-and-mycotoxin-production
#7
Caterina Morcia, Giorgio Tumino, Roberta Ghizzoni, Assetou Bara, Nesrine Salhi, Valeria Terzi
Phytopathogenic fungi can lead to significant cereal yield losses, also producing mycotoxins dangerous for human and animal health. The fungal control based on the use of synthetic fungicides can be complemented by "green" methods for crop protection, based on the use of natural products. In this frame, the antifungal activities of bergamot and lemon essential oils and of five natural compounds recurrent in essential oils (citronellal, citral, cinnamaldehyde, cuminaldehyde and limonene) have been evaluated against three species of mycotoxigenic fungi (Fusarium sporotrichioides, F...
July 29, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28756770/synthetic-lethal-short-hairpin-rna-screening-reveals-that-ring-finger-protein-183-confers-resistance-to-trametinib-in-colorectal-cancer-cells
#8
Rong Geng, Xin Tan, Zhixiang Zuo, Jiangxue Wu, Zhizhong Pan, Wei Shi, Ranyi Liu, Chen Yao, Gaoyuan Wang, Jiaxin Lin, Lin Qiu, Wenlin Huang, Shuai Chen
BACKGROUND: The mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer (CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells, using a synthetic lethal short hairpin RNA (shRNA) screening approach...
July 31, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/28756516/synthetic-lethality-in-malignant-pleural-mesothelioma-with-parp1-inhibition
#9
Gayathri Srinivasan, Gurjit Singh Sidhu, Elizabeth A Williamson, Aruna S Jaiswal, Nasreen Najmunnisa, Keith Wilcoxen, Dennie Jones, Thomas J George, Robert Hromas
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers...
July 29, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28754723/a-functional-link-between-bir1-and-the-saccharomyces-cerevisiae-ctf19-kinetochore-complex-revealed-through-quantitative-fitness-analysis
#10
Vasso Makrantoni, Adam Ciesiolka, Conor Lawless, Josefin Fernius, Adele Marston, David Lydall, Michael J R Stark
The chromosomal passenger complex (CPC) is a key regulator of eukaryotic cell division, consisting of the protein kinase Aurora B/Ipl1 in association with its activator (INCENP/Sli15) and two additional proteins (Survivin/Bir1 and Borealin/Nbl1). Here we report a genome-wide genetic interaction screen in Saccharomyces cerevisiae using the bir1-17 mutant, identifying through quantitative fitness analysis deletion mutations that act as enhancers and suppressors. Gene knockouts affecting the Ctf19 kinetochore complex were identified as the strongest enhancers of bir1-17, while mutations affecting the large ribosomal subunit or the mRNA nonsense-mediated decay (NMD) pathway caused strong phenotypic suppression...
July 28, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28754563/changes-in-gene-expression-variability-reveal-a-stable-synthetic-lethal-interaction-network-in-brca2-ovarian-cancers
#11
Raymund Bueno, Jessica C Mar
Synthetic lethal interactions (SLIs) are robust mechanisms that provide cells with the ability to sustain viability despite having mutations in genes critical to the DNA damage response, a core cellular process. Studies in model organisms such as S. cerevisiae showed that thousands of genes important in maintaining DNA integrity cooperated in a SLI network. Two genes participate in a SLI when mutation in one gene has no effect on the cell, but mutations in both interacting genes are lethal. Furthermore in C...
July 25, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28753431/project-drive-a-compendium-of-cancer-dependencies-and-synthetic-lethal-relationships-uncovered-by-large-scale-deep-rnai-screening
#12
E Robert McDonald, Antoine de Weck, Michael R Schlabach, Eric Billy, Konstantinos J Mavrakis, Gregory R Hoffman, Dhiren Belur, Deborah Castelletti, Elizabeth Frias, Kalyani Gampa, Javad Golji, Iris Kao, Li Li, Philippe Megel, Thomas A Perkins, Nadire Ramadan, David A Ruddy, Serena J Silver, Sosathya Sovath, Mark Stump, Odile Weber, Roland Widmer, Jianjun Yu, Kristine Yu, Yingzi Yue, Dorothee Abramowski, Elizabeth Ackley, Rosemary Barrett, Joel Berger, Julie L Bernard, Rebecca Billig, Saskia M Brachmann, Frank Buxton, Roger Caothien, Justina X Caushi, Franklin S Chung, Marta Cortés-Cros, Rosalie S deBeaumont, Clara Delaunay, Aurore Desplat, William Duong, Donald A Dwoske, Richard S Eldridge, Ali Farsidjani, Fei Feng, JiaJia Feng, Daisy Flemming, William Forrester, Giorgio G Galli, Zhenhai Gao, François Gauter, Veronica Gibaja, Kristy Haas, Marc Hattenberger, Tami Hood, Kristen E Hurov, Zainab Jagani, Mathias Jenal, Jennifer A Johnson, Michael D Jones, Avnish Kapoor, Joshua Korn, Jilin Liu, Qiumei Liu, Shumei Liu, Yue Liu, Alice T Loo, Kaitlin J Macchi, Typhaine Martin, Gregory McAllister, Amandine Meyer, Sandra Mollé, Raymond A Pagliarini, Tanushree Phadke, Brian Repko, Tanja Schouwey, Frances Shanahan, Qiong Shen, Christelle Stamm, Christine Stephan, Volker M Stucke, Ralph Tiedt, Malini Varadarajan, Kavitha Venkatesan, Alberto C Vitari, Marco Wallroth, Jan Weiler, Jing Zhang, Craig Mickanin, Vic E Myer, Jeffery A Porter, Albert Lai, Hans Bitter, Emma Lees, Nicholas Keen, Audrey Kauffmann, Frank Stegmeier, Francesco Hofmann, Tobias Schmelzle, William R Sellers
Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines...
July 27, 2017: Cell
https://www.readbyqxmd.com/read/28749464/the-cohesin-complex-prevents-myc-induced-replication-stress
#13
Sara Rohban, Aurora Cerutti, Marco J Morelli, Fabrizio d'Adda di Fagagna, Stefano Campaner
The cohesin complex is mutated in cancer and in a number of rare syndromes collectively known as Cohesinopathies. In the latter case, cohesin deficiencies have been linked to transcriptional alterations affecting Myc and its target genes. Here, we set out to understand to what extent the role of cohesins in controlling cell cycle is dependent on Myc expression and activity. Inactivation of the cohesin complex by silencing the RAD21 subunit led to cell cycle arrest due to both transcriptional impairment of Myc target genes and alterations of replication forks, which were fewer and preferentially unidirectional...
July 27, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28744260/pipy-a-member-of-the-conserved-cog0325-family-of-plp-binding-proteins-expands-the-cyanobacterial-nitrogen-regulatory-network
#14
José I Labella, Raquel Cantos, Javier Espinosa, Alicia Forcada-Nadal, Vicente Rubio, Asunción Contreras
Synechococcus elongatus PCC 7942 is a paradigmatic model organism for nitrogen regulation in cyanobacteria. Expression of genes involved in nitrogen assimilation is positively regulated by the 2-oxoglutarate receptor and global transcriptional regulator NtcA. Maximal activation requires the subsequent binding of the co-activator PipX. PII, a protein found in all three domains of life as an integrator of signals of the nitrogen and carbon balance, binds to PipX to counteract NtcA activity at low 2-oxoglutarate levels...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28743817/bacterial-signaling-nucleotides-inhibit-yeast-cell-growth-by-impacting-mitochondrial-and-other-specifically-eukaryotic-functions
#15
Andy Hesketh, Marta Vergnano, Chris Wan, Stephen G Oliver
We have engineered Saccharomyces cerevisiae to inducibly synthesize the prokaryotic signaling nucleotides cyclic di-GMP (cdiGMP), cdiAMP, and ppGpp in order to characterize the range of effects these nucleotides exert on eukaryotic cell function during bacterial pathogenesis. Synthetic genetic array (SGA) and transcriptome analyses indicated that, while these compounds elicit some common reactions in yeast, there are also complex and distinctive responses to each of the three nucleotides. All three are capable of inhibiting eukaryotic cell growth, with the guanine nucleotides exhibiting stronger effects than cdiAMP...
July 25, 2017: MBio
https://www.readbyqxmd.com/read/28742144/genome-wide-and-protein-kinase-focused-rnai-screens-reveal-conserved-and-novel-damage-response-pathways-in-trypanosoma-brucei
#16
Jennifer A Stortz, Tiago D Serafim, Sam Alsford, Jonathan Wilkes, Fernando Fernandez-Cortes, Graham Hamilton, Emma Briggs, Leandro Lemgruber, David Horn, Jeremy C Mottram, Richard McCulloch
All cells are subject to structural damage that must be addressed for continued growth. A wide range of damage affects the genome, meaning multiple pathways have evolved to repair or bypass the resulting DNA lesions. Though many repair pathways are conserved, their presence or function can reflect the life style of individual organisms. To identify genome maintenance pathways in a divergent eukaryote and important parasite, Trypanosoma brucei, we performed RNAi screens to identify genes important for survival following exposure to the alkylating agent methyl methanesulphonate...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28742068/a-peptide-based-viral-inactivator-inhibits-zika-virus-infection-in-pregnant-mice-and-fetuses
#17
Yufeng Yu, Yong-Qiang Deng, Peng Zou, Qian Wang, Yanyan Dai, Fei Yu, Lanying Du, Na-Na Zhang, Min Tian, Jia-Nan Hao, Yu Meng, Yuan Li, Xiaohui Zhou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Cheng-Feng Qin, Shibo Jiang, Lu Lu
Zika virus (ZIKV), a re-emerging flavivirus associated with neurological disorders, has spread rapidly to more than 70 countries and territories. However, no specific vaccines or antiviral drugs are currently available to prevent or treat ZIKV infection. Here we report that a synthetic peptide derived from the stem region of ZIKV envelope protein, designated Z2, potently inhibits infection of ZIKV and other flaviviruses in vitro. We show that Z2 interacts with ZIKV surface protein and disrupts the integrity of the viral membrane...
July 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28741798/novel-orally-bioavailable-ezh1-2-dual-inhibitors-with-greater-antitumor-efficacy-than-an-ezh2-selective-inhibitor
#18
Daisuke Honma, Osamu Kanno, Jun Watanabe, Junzo Kinoshita, Makoto Hirasawa, Emi Nosaka, Machiko Shiroishi, Takeshi Takizawa, Isao Yasumatsu, Takao Horiuchi, Akira Nakao, Keisuke Suzuki, Tomonori Yamasaki, Katsuyoshi Nakajima, Miho Hayakawa, Takanori Yamazaki, Ajay Singh Yadav, Nobuaki Adachi
Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis...
July 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28741503/the-pushmi-pullyu-of-dna-repair-clinical-synthetic-lethality
#19
REVIEW
S Percy Ivy, Johann de Bono, Elise C Kohn
Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in the genome caused by cancer and cancer treatment provides therapeutic opportunities to leverage the critical balance between DNA injury and repair. Blocking repair and pushing damaged DNA through the cell cycle using therapeutic inhibitors exemplify the 'pushmi-pullyu' effect of disrupted DNA repair. DNA repair inhibitors (DNARi) can be separated into five biofunctional categories: sensors, mediators, transducers, effectors, and collaborators that recognize DNA damage, propagate injury DNA messages, regulate cell cycle checkpoints, and alter the microenvironment...
November 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28735000/application-of-pharmacometrics-and-quantitative-systems-pharmacology-to-cancer-therapy-the-example-of-luminal-a-breast-cancer
#20
REVIEW
Brett Fleisher, Ashley N Brown, Sihem Ait-Oudhia
Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs' efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC...
July 19, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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