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actionable mutation

Darja Pollpeter, Andrew Sobala, Michael H Malim
Monitoring of nucleic acid intermediates during virus replication provides insights into the effects and mechanisms of action of antiviral compounds and host cell proteins on viral DNA synthesis. Here we address the lack of a cell-based, high-coverage, and high-resolution assay that is capable of defining retroviral reverse transcription intermediates within the physiological context of virus infection. The described method captures the 3'-termini of nascent complementary DNA (cDNA) molecules within HIV-1 infected cells at single nucleotide resolution...
January 30, 2019: Journal of Visualized Experiments: JoVE
Bo Tang, Yushuang Hu, Zhijie Wang, Chen Cheng, Pengyun Wang, Lina Liang, Hongbo Xiong, Chunyan Luo, Chengqi Xu, Qiuyun Chen, Qing Kenneth Wang
Voltage-gated sodium channel Nav 1.5 is critical for generation and conduction of cardiac action potentials. Mutations and expression level changes of Nav 1.5 are associated with cardiac arrhythmias and sudden death. The ubiquitin (Ub) conjugation machinery utilizes three enzyme activities, E1, E2, and E3, to regulate protein degradation. Previous studies from us and others showed that Nedd4-2 acts as an E3 ubiquitin-protein ligase involved in ubiquitination and degradation of Nav 1.5, however, more key regulators remain to be identified...
February 14, 2019: Journal of Molecular and Cellular Cardiology
Ralf Buettner, Le Xuan Truong Nguyen, Bijender Kumar, Corey Morales, Chao Liu, Lisa S Chen, Tea Pemovska, Timothy W Synold, Joycelynne Palmer, Ryan Thompson, Ling Li, Dinh Hoa Hoang, Bin Zhang, Lucy Ghoda, Claudia Kowolik, Mika Kontro, Calum Leitch, Krister Wennerberg, Xiaochun Xu, Ching-Cheng Chen, David Horne, Varsha Gandhi, Vinod Pullarkat, Guido Marcucci, Steven T Rosen
Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription...
February 15, 2019: Journal of Cellular Physiology
Dominic H Banda, Paula M Perin, Richard J P Brown, Daniel Todt, Wladimir Solodenko, Patrick Hoffmeyer, Kamlesh Kumar Sahu, Michael Houghton, Philip Meuleman, Rolf Müller, Andreas Kirschning, Thomas Pietschmann
BACKGROUND & AIMS: Hepatitis C virus infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors representing candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. METHODS: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations...
February 12, 2019: Journal of Hepatology
J Key, A K Mueller, S Gispert, L Matschke, I Wittig, O Corti, C Münch, N Decher, G Auburger
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy. We attempted to go beyond previous work mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase...
February 11, 2019: Neurobiology of Disease
Tetyana Kobets, Gary M Williams
In the deliberations over many years on the question of thresholds for the carcinogenicity of chemicals, the dominant paradigm has been the linear no-threshold (LNT) model, derived from concepts formulated in radiation mutagenicity. Based on the analogy with radiation, the key mechanistic assumption underlying the assessment of the dose-effect of chemical-induced carcinogenicity has been that any dose, no matter how low, can lead to induction of mutations, which will result in some risk of neoplasia. The LNT assumption, however, was never well founded and, its application to chemical carcinogens, does not allow for differences in their disposition or mechanisms of action...
November 28, 2018: Chemico-biological Interactions
Samantha X Y Wang, Bing M Zhang, Heather A Wakelee, Michael Z Koontz, MingGui Pan, Maximilian Diehn, Christian A Kunder, Joel W Neal
The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review...
February 12, 2019: Anti-cancer Drugs
Sarah E Burkhart, Roxanna J Llinas, Bonnie Bartel
Peroxisomes rely on peroxins (PEX proteins) for biogenesis, importing membrane and matrix proteins, and fission. PEX16, which is implicated in peroxisomal membrane protein targeting and forming nascent peroxisomes from the endoplasmic reticulum (ER), is unusual among peroxins because it is inserted co-translationally into the ER and localizes to both ER and peroxisomal membranes. PEX16 mutations in humans, yeast, and plants confer some common peroxisomal defects; however, apparent functional differences have impeded the development of a unified model for PEX16 action...
February 14, 2019: Journal of Integrative Plant Biology
Andrew M Wollacott, Luke N Robinson, Boopathy Ramakrishnan, Hamid Tissire, Karthik Viswanathan, Zachary Shriver, Gregory J Babcock
IgA nephropathy (IgAN) is the most prevalent cause of primary glomerular disease worldwide, and the cytokine A PRoliferation-Inducing Ligand (APRIL) is emerging as a key player in IgAN pathogenesis and disease progression. For a panel of anti-human APRIL antibodies with known antagonistic activity, we sought to define their structural mode of engagement to understand molecular mechanisms of action and aid rational antibody engineering. Reliable computational prediction of antibody-antigen complexes remains challenging, and experimental methods such as X-ray co-crystallography and cryoEM have considerable technical, resource, and throughput barriers...
February 13, 2019: Journal of Molecular Recognition: JMR
Fernando Sanz-García, Ernesto Anoz-Carbonell, Esther Pérez-Herrán, Carlos Martín, Ainhoa Lucía, Liliana Rodrigues, José A Aínsa
Aminoglycoside acetyltransferases are important determinants of resistance to aminoglycoside antibiotics in most bacterial genera. In mycobacteria, however, aminoglycoside acetyltransferases contribute only partially to aminoglycoside susceptibility since they are related with low level resistance to these antibiotics (while high level aminoglycoside resistance is due to mutations in the ribosome). Instead, aminoglycoside acetyltransferases contribute to other bacterial functions, and this can explain its widespread presence along species of genus Mycobacterium ...
2019: Frontiers in Microbiology
Igor B Rogozin, Abiel Roche-Lima, Artem G Lada, Frida Belinky, Ivan A Sidorenko, Galina V Glazko, Vladimir N Babenko, David N Cooper, Youri I Pavlov
Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type...
February 12, 2019: Cancers
Nadia Bouhamdani, Dominique Comeau, Kevin Cormier, Sandra Turcotte
Autophagy is a highly conserved, homeostatic process by which cytosolic components reach lysosomes for degradation. The roles that play different autophagic processes in cancer are complex and remain cancer-type and -stage dependent. Renal cell carcinoma (RCC) is the most common subtype of kidney cancer and is characterized by the inactivation of the VHL tumor suppressor. Our previous study identified a small compound, STF-62247 as an autophagy-modulating molecule causing selective cytotoxicity for VHL-inactivated cells...
February 13, 2019: American Journal of Physiology. Cell Physiology
Nathaniel Edward Bennett Saidu, Niloufar Kavian, Karen Leroy, Claus Jacob, Carole Nicco, Frédéric Batteux, Jérôme Alexandre
Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine-rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose-dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2...
February 12, 2019: Medicinal Research Reviews
Kimberli J Kamer, Wei Jiang, Virendar K Kaushik, Vamsi K Mootha, Zenon Grabarek
The mitochondrial uniporter is a Ca2+ -channel complex resident within the organelle's inner membrane. In mammalian cells the uniporter's activity is regulated by Ca2+ due to concerted action of MICU1 and MICU2, two paralogous, but functionally distinct, EF-hand Ca2+ -binding proteins. Here we present the X-ray structure of the apo form of Mus musculus MICU2 at 2.5-Å resolution. The core structure of MICU2 is very similar to that of MICU1. It consists of two lobes, each containing one canonical Ca2+ -binding EF-hand (EF1, EF4) and one structural EF-hand (EF2, EF3)...
February 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
Vid Mlakar, Simona Jurkovic Mlakar, Laurence Lesne, Denis Marino, Komal S Rathi, John M Maris, Marc Ansari, Fabienne Gumy-Pause
BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children. This cancer has a low frequency of TP53 mutations and its downstream pathway is usually intact. This study assessed the efficacy of the p53 activator, PRIMA-1MET , in inducing neuroblastoma cell death. METHODS: CellTiter 2.0 was used to study susceptibility and specificity of NB cell lines to PRIMA-1MET . Real-time PCR and western blot were used to assess the most common p53 transactivation targets...
February 12, 2019: Journal of Experimental & Clinical Cancer Research: CR
Xiangyang Li, April Z Gu, Ye Zhang, Bin Xie, Dan Li, Jianmin Chen
The emergence of antibiotic resistance is a growing problem worldwide. Numerous studies have demonstrated that heavy metals facilitate the spread of bacterial drug-resistance in the environment. However, the actions and mechanisms of metals at relatively low sub-lethal levels (far below the minimal inhibitory concentration [MIC]) on antibiotic resistance remain unclear. In this study, we investigated the effect of sub-lethal levels of heavy metals [Ag(I), Zn(II), and Cu(II)] on antibiotic resistance and explored the underlying mechanisms...
February 4, 2019: Journal of Hazardous Materials
Beth L Dumont
Mutation provides the ultimate source of all new alleles in populations, including variants that cause disease and fuel adaptation. Recent whole genome sequencing studies have uncovered variation in the mutation rate among individuals and differences in the relative frequency of specific nucleotide changes (the mutation spectrum) between populations. Although parental age is a major driver of differences in overall mutation rate among individuals, the causes of variation in the mutation spectrum remain less well understood...
February 11, 2019: Molecular Biology and Evolution
Gabriel E Rech, María Bogaerts-Márquez, Maite G Barrón, Miriam Merenciano, José Luis Villanueva-Cañas, Vivien Horváth, Anna-Sophie Fiston-Lavier, Isabelle Luyten, Sandeep Venkataram, Hadi Quesneville, Dmitri A Petrov, Josefa González
Most of the current knowledge on the genetic basis of adaptive evolution is based on the analysis of single nucleotide polymorphisms (SNPs). Despite increasing evidence for their causal role, the contribution of structural variants to adaptive evolution remains largely unexplored. In this work, we analyzed the population frequencies of 1,615 Transposable Element (TE) insertions annotated in the reference genome of Drosophila melanogaster, in 91 samples from 60 worldwide natural populations. We identified a set of 300 polymorphic TEs that are present at high population frequencies, and located in genomic regions with high recombination rate, where the efficiency of natural selection is high...
February 2019: PLoS Genetics
Peter Rotwein
Repulsive guidance molecules, RGMA, RGMB, and RGMC, are related proteins discovered independently through different experimental paradigms. They are encoded by single copy genes in mammalian and other vertebrate genomes, and are ~50% identical in amino acid sequence. The importance of RGM actions in human physiology has not been realized, as most research has focused on non-human models, although mutations in RGMC are the cause of the severe iron storage disorder, juvenile hemochromatosis. Here I show that repositories of human genomic and population genetic data can be used as starting points for discovery and for developing new testable hypotheses about each of these paralogs in human biology and disease susceptibility...
February 2019: Physiological Reports
Htut Htut Htoo, Lauren Brumage, Vorrapon Chaikeeratisak, Hannah Tsunemoto, Joseph Sugie, Chanwit Tribuddharat, Joe Pogliano, Poochit Nonejuie
An increasing number of multidrug-resistant Acinetobacter baumannii (MDR- AB ) infections have been reported worldwide, posing a threat to public health. The establishment of methods to elucidate the mechanism of action (MOA) of A. baumannii -specific antibiotics is needed to develop novel antimicrobial therapeutics with activity against MDR- AB We previously developed bacterial cytological profiling (BCP) to understand the MOA of compounds in E. coli and B. subtilis Given how distantly related A. baumannii is to these species, it was unclear to what extent it could be applied...
February 11, 2019: Antimicrobial Agents and Chemotherapy
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