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Synthetic lethality

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https://www.readbyqxmd.com/read/28523286/synthetic-lethality-screens-using-rnai-in-combination-with-crispr-based-knockout-in-drosophila-cells
#1
Benjamin E Housden, Hilary E Nicholson, Norbert Perrimon
A synthetic lethal interaction is a type of genetic interaction where the disruption of either of two genes individually has little effect but their combined disruption is lethal. Knowledge of synthetic lethal interactions can allow for elucidation of network structure and identification of candidate drug targets for human diseases such as cancer. In Drosophila, combinatorial gene disruption has been achieved previously by combining multiple RNAi reagents. Here we describe a protocol for high-throughput combinatorial gene disruption by combining CRISPR and RNAi...
February 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#2
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28521333/drugging-the-cancers-addicted-to-dna-repair
#3
Jac A Nickoloff, Dennie Jones, Suk-Hee Lee, Elizabeth A Williamson, Robert Hromas
Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality)...
November 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28510338/therapeutic-targeting-of-poly-adp-ribose-polymerase-1-in-cancer-current-developments-therapeutic-strategies-and-future-opportunities
#4
REVIEW
Jyotika Rajawat, Nidhi Shukla, Durga Prasad Mishra
Poly(ADP-ribose) polymerase-1 (PARP1) is key protein involved in numerous cellular processes including DNA repair, replication, and transcription. PARP interacts directly, indirectly, or via PARylation with various oncogenic proteins and regulates several transcription factors, thereby modulating carcinogenesis. Therapeutic inhibition of PARP is therefore perceived as a promising anticancer strategy, and a number of PARP inhibitors (PARPi) are in different stages of clinical evaluation. PARPi inhibit the DNA repair pathway and thus form the concept of synthetic lethality in cancer therapeutics...
May 16, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28500265/acyl-coa-binding-protein-acbp1-modulates-sterol-synthesis-during-embryogenesis
#5
Shiu-Cheung Lung, Pan Liao, Edward Chee-Tak Yeung, An-Shan Hsiao, Yan Xue, Mee-Len Chye
Fatty acids (FAs) and sterols are primary metabolites that exert interrelated functions as structural and signaling lipids. Despite their common syntheses from acetyl-CoA, homeostatic crosstalk remains enigmatic. Six Arabidopsis acyl-CoA-binding proteins (ACBPs) are involved in FA metabolism. ACBP1 interacts with PHOSPHOLIPASE Dα1 and regulates phospholipid composition. Herein, its specific role in negative modulation of sterol synthesis during embryogenesis is reported. ACBP1, likely in a liganded state, interacts with STEROL C4-METHYL OXIDASE1-1 (SMO1-1), a rate-limiting enzyme in the sterol pathway...
May 12, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28499277/ppars-as-determinants-of-the-estrogen-receptor-lineage-use-of-synthetic-lethality-for-the-treatment-of-estrogen-receptor-negative-breast-cancer
#6
Robert I Glazer, Levy Kopelovich
The Dilemma: Estrogen receptora-negative (ER-) breast cancer lacks a specific critical target to control tumor progression. THE OBJECTIVE: To identify mechanisms that enable increased expression of the ER+ lineage in an otherwise ER- breast cancer.Preface: The nuclear receptor superfamily members PPARγ and PPARδ regulate gene expression associated with a multitude of pathways, including intermediary metabolism, angiogenesis, proliferation and inflammation (see reviews [1-3]). Recent developments using transgenic and knockout mice, as well as pharmacologic intervention with PPARγ and PPARδ agonists, have revealed a previously unknown relationship between PPARγ suppression and PPARδ activation that leads to the appearance of ER+ tumors, enabling a synthetic lethality approach by anti-ER therapy...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28498362/caspases-and-their-substrates
#7
REVIEW
Olivier Julien, James A Wells
Protease biology is intimately linked to the functional consequences of substrate cleavage events. Human caspases are a family of 12 fate-determining cysteine proteases that are best known for driving cell death, either apoptosis or pyroptosis. More recently, caspases have been shown to be involved in other cellular remodeling events as well including stem cell fate determination, spermatogenesis, and erythroid differentiation. Recent global proteomics methods enable characterization of the substrates that caspases cleave in live cells and cell extracts...
May 12, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28497778/pten-regulates-glioblastoma-oncogenesis-through-chromatin-associated-complexes-of-daxx-and-histone-h3-3
#8
Jorge A Benitez, Jianhui Ma, Matteo D'Antonio, Antonia Boyer, Maria Fernanda Camargo, Ciro Zanca, Stephen Kelly, Alireza Khodadadi-Jamayran, Nathan M Jameson, Michael Andersen, Hrvoje Miletic, Shahram Saberi, Kelly A Frazer, Webster K Cavenee, Frank B Furnari
Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN (phosphatase and tensin homolog) are frequent events and are associated with therapeutic resistance. Herein, we report a novel chromatin-associated function of PTEN in complex with the histone chaperone DAXX and the histone variant H3.3. We show that PTEN interacts with DAXX and, in turn PTEN directly regulates oncogene expression by modulating DAXX-H3.3 association on the chromatin, independently of PTEN enzymatic activity...
May 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28494239/crispr-cas9-screens-reveal-epstein-barr-virus-transformed-b-cell-host-dependency-factors
#9
Yijie Ma, Michael J Walsh, Katharina Bernhardt, Camille W Ashbaugh, Stephen J Trudeau, Isabelle Y Ashbaugh, Sizun Jiang, Chang Jiang, Bo Zhao, David E Root, John G Doench, Benjamin E Gewurz
Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (BL) and immunosuppression-related lymphomas. These B cell malignancies arise by distinct transformation pathways and have divergent viral and host expression programs. To identify host dependency factors resulting from these EBV+, B cell-transformed cell states, we performed parallel genome-wide CRISPR/Cas9 loss-of-function screens in BL and lymphoblastoid cell lines (LCLs). These highlighted 57 BL and 87 LCL genes uniquely important for their growth and survival...
May 10, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28486691/combined-kinase-inhibitors-of-mek1-2-and-either-pi3k-or-pdgfr-are-efficacious-in-intracranial-triple-negative-breast-cancer
#10
Amanda E D Van Swearingen, Maria J Sambade, Marni B Siegel, Shivani Sud, Robert S McNeill, Samantha M Bevill, Xin Chen, Ryan E Bash, Louisa Mounsey, Brian T Golitz, Charlene Santos, Allison Deal, Joel S Parker, Naim Rashid, C Ryan Miller, Gary L Johnson, Carey K Anders
Background: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases...
May 9, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28484009/in-vivo-engineering-of-bone-tissues-with-hematopoietic-functions-and-mixed-chimerism
#11
Yu-Ru Shih, Heemin Kang, Vikram Rao, Yu-Jui Chiu, Seong Keun Kwon, Shyni Varghese
Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures...
May 8, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28483525/the-two-transmembrane-regions-of-candida-albicans-dfi1-contribute-to-its-biogenesis
#12
Sanna E Herwald, Paola C Zucchi, Shumin Tan, Carol A Kumamoto
The opportunistic pathogen Candida albicans forms invasive filaments that grow into host tissues during disease. The glycosylated, integral plasma membrane protein Dfi1 is important for invasive filamentation in a laboratory model, and for lethality in murine disseminated candidiasis. However, Dfi1 topology and essential domains for Dfi1 biogenesis were undefined. Sequence analysis predicted that Dfi1 contains two transmembrane regions, located near the N- and C-termini. In this communication, we show that Dfi1 remains an integral membrane protein despite deletion of either predicted transmembrane region, whereas deletion of both regions results in a soluble protein...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#13
Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Grazyna Hoser, Silvia Maifrede, Esteban Martinez, Daniela Di Marcantonio, Elisabeth Bolton-Gillespie, Kimberly Cramer-Morales, Jaewong Lee, Min Li, Artur Slupianek, Daniel Gritsyuk, Sabine Cerny-Reiterer, Ilona Seferynska, Tomasz Stoklosa, Lars Bullinger, Huaqing Zhao, Vera Gorbunova, Katarzyna Piwocka, Peter Valent, Curt I Civin, Markus Muschen, John E Dick, Jean C Y Wang, Smita Bhatia, Ravi Bhatia, Kolia Eppert, Mark D Minden, Stephen M Sykes, Tomasz Skorski
Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28477111/atm-kinase-inhibitors-hts-cellular-imaging-assay-using-cellomics%C3%A2-arrayscan-vti-platform
#14
Catherine Bardelle, Joanna Boros
Small molecule inhibitors of the ATM pathway could represent a promising opportunity for cancer therapy, working either by enhancing the clinical efficacy of radiotherapy and existing chemotherapies or by synthetic lethality-based mechanisms. In this chapter, we describe a high-throughput, high-content imaging assay monitoring levels of ATM phosphorylation at Serine 1981 following induction of DNA damage by ionizing radiation.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28475612/calmodulin-like-proteins-localized-to-the-conoid-regulate-motility-and-cell-invasion-by-toxoplasma-gondii
#15
Shaojun Long, Kevin M Brown, Lisa L Drewry, Bryan Anthony, Isabelle Q H Phan, L David Sibley
Toxoplasma gondii contains an expanded number of calmodulin (CaM)-like proteins whose functions are poorly understood. Using a combination of CRISPR/Cas9-mediated gene editing and a plant-like auxin-induced degron (AID) system, we examined the roles of three apically localized CaMs. CaM1 and CaM2 were individually dispensable, but loss of both resulted in a synthetic lethal phenotype. CaM3 was refractory to deletion, suggesting it is essential. Consistent with this prediction auxin-induced degradation of CaM3 blocked growth...
May 5, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28475173/microrna-30a-attenuates-mutant-kras-driven-colorectal-tumorigenesis-via-direct-suppression-of-me1
#16
Hongxing Shen, Chuan Xing, Kaisa Cui, Yunxiao Li, Jinxiang Zhang, Runlei Du, Xiaodong Zhang, Youjun Li
Frequent KRAS mutations contribute to multiple cancers including ~40% of human colorectal cancers (CRCs). Systematic screening of 1255 microRNAs (miRNAs) identified miR-30a as a synthetic lethal in KRAS-mutant CRC cells. miR-30a was downregulated in CRCs and repressed by P65. miR-30a directly targeted malic enzyme 1 (ME1) and KRAS, and inhibited anchorage-independent growth and in vivo tumorigenesis by KRAS-mutant CRC cells. ME1 was significantly upregulated in KRAS-mutant CRCs. Eliminating ME1 by short hairpin RNA (shRNA) resulted in obviously decreased NADPH production, levels of triglyceride and fatty acid, and an inhibition of tumorigenicity of KRAS-mutant CRCs...
May 5, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28469491/synthetic-growth-hormone-releasing-peptides-ghrps-a-historical-appraisal-of-the-evidences-supporting-their-cytoprotective-effects
#17
REVIEW
Jorge Berlanga-Acosta, Angel Abreu-Cruz, Diana García-Del Barco Herrera, Yssel Mendoza-Marí, Arielis Rodríguez-Ulloa, Ariana García-Ojalvo, Viviana Falcón-Cama, Francisco Hernández-Bernal, Qu Beichen, Gerardo Guillén-Nieto
BACKGROUND: Growth hormone-releasing peptides (GHRPs) constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium...
2017: Clinical Medicine Insights. Cardiology
https://www.readbyqxmd.com/read/28468827/hmg-coa-synthase-1-is-a-synthetic-lethal-partner-of-braf-v600e-in-human-cancers
#18
Liang Zhao, Jun Fan, Siyuan Xia, Yaozhu Pan, Shuangping Liu, Guoqing Qian, Zhiyu Qian, Hee-Bum Kang, Jack L Arbiser, Brian P Pollack, Ragini Kudchadkar, David H Lawson, Michael Rossi, Omar Abdel-Wahab, Taha Merghoub, Hanna J Khoury, Fadlo R Khuri, Lawrence H Boise, Sagar Lonial, Fangping Chen, Jing Chen, Ruiting Lin
Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAF(V600E) upregulates HMG-CoA lyase (HMGCL), which converts HMG-CoA to acetyl-CoA and a ketone body, acetoacetate, that selectively enhances BRAFV600E-dependent MEK1 activation in human cancer...
May 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28468764/a-resource-for-functional-profiling-of-noncoding-rna-in-the-yeast-saccharomyces-cerevisiae
#19
Steven Parker, Marcin Fraczek, Jian Wu, Sara Shamsah, Alkisti Manousaki, Kobchai Dungrattanalert, Rogerio Alves de Almeida, Diego Estrada-Rivadeneyra, Walid Omara, Daniela Delneri, Raymond T O'Keefe
Eukaryotic genomes are extensively transcribed generating many different RNAs with no known function. We have constructed 1502 molecular barcoded ncRNA gene deletion strains encompassing 443 ncRNAs in the yeast Saccharomyces cerevisiae as tools for ncRNA functional analysis. This resource includes deletions of small nuclear RNAs (snRNAs), transfer RNAs (tRNAs), small nucleolar RNAs (snoRNAs) and other annotated ncRNAs as well as the more recently identified stable unannotated transcripts (SUTs) and cryptic unstable transcripts (CUTs) whose functions are largely unknown...
May 3, 2017: RNA
https://www.readbyqxmd.com/read/28467918/higher-antitumor-activity-of-trabectedin-in-germline-brca2-carriers-with-advanced-breast-cancer-as-compared-to-brca1-carriers-a-subset-analysis-of-a-dedicated-phase-ii-trial
#20
Amal Ghouadni, Suzette Delaloge, Pilar Lardelli, Carmen Kahatt, Tomasz Byrski, Joanne L Blum, Anthony Gonçalves, Mario Campone, Antonio Nieto, Vicente Alfaro, Martin Cullell-Young, Jan Lubinski
Specific alkylators may allow synthetic lethality among patients with germline BRCA1/2-mutations related cancers. The tetrahydroisoquinolone trabectedin administered at 1.3 mg/m(2) as a 3-h intravenous infusion every 3 weeks showed activity in patients with pretreated metastatic breast cancer (MBC) and BRCA germline mutations, but mainly in BRCA2 carriers. Data from a phase II study were retrospectively analyzed to compare the efficacy and safety of this trabectedin dose and schedule in pretreated MBC patients bearing germline BRCA1/2 mutations...
April 30, 2017: Breast: Official Journal of the European Society of Mastology
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