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RNA helicases constitute a large family of proteins that play critical roles in mediating RNA function. They have been implicated in all facets of gene expression pathways involving RNA, from transcription to processing, transport and translation, and storage and decay. There is significant interest in developing small molecule inhibitors to RNA helicases as some family members have been documented to be dysregulated in neurological and neurodevelopment disorders, as well as in cancers. Although different functional properties of RNA helicases offer multiple opportunities for small molecule development, molecular staples have recently come to the forefront. These bifunctional molecules interact with both protein and RNA components to lock them together, thereby imparting novel gain-of-function properties to their targets. This article is categorized under: RNA Interactions with Proteins and Other MoleculesSmall Molecule-RNA Interactions RNA Interactions with Proteins and Other MoleculesProtein-RNA Interactions: Functional Implications.

Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC50 growth inhibitory values between 30–100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine.—Van Goietsenoven, G., Hutton, J., Becker, J.-P., Lallemand, B., Robert, F., Lefranc, F., Pirker, C., Vandenbussche, G., Van Antwerpen, P., Evidente, A., Berger, W., Prévost, M., Pelletier, J., Kiss, R., Goss Kinzy, T., Kornienko, A., Mathieu, V. Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas.

Helicases are implicated in most stages of the gene expression pathway, ranging from DNA replication, RNA transcription, splicing, RNA transport, ribosome biogenesis, mRNA translation, RNA storage and decay. These enzymes utilize energy derived from nucleotide triphosphate hydrolysis to remodel ribonucleoprotein complexes, RNA, or DNA and in this manner affect the information content or output of RNA. Several RNA helicases have been implicated in the oncogenic process—either through altered expression levels, mutations, or due to their role in pathways required for tumor initiation, progression, maintenance, or chemosensitivity. The purpose of this review is to highlight those RNA helicases for which there is significant evidence implicating them in cancer biology. WIREs RNA 2013, 4:333–349. doi: 10.1002/wrna.1163 The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.

Projected increasing temperatures and reduced summer rainfall in the UK pose a sustainability and food security challenge for the agricultural industry. This study investigates the potential impact of precipitation changes on Eastern England sugar beet yield. Precipitation data over Eastern England from weather stations (1971-2000) and a range of CMIP5 climate models (“historical” for 1971-2000; and RCP45 and RCP85 for 2021-2050) were examined. A good agreement was found between the observations and the overlapping model grid cell. The study then investigated the impact of likely future rainfall changes on yield by applying controlled watering regimes informed by the CMIP5 projections 10 to 150 sugar beet plants grown in a greenhouse – the use of CMIP5 projections in this way is a first. Watering regimes that represent “present day” and “future” precipitation characteristics were calculated: 0.46L of water was applied every other day to each plant in the “present day” category; 0.39L was applied every other day to each plant in the “future” category. This reflects the 16% reduction in future rainfall that was calculated from the climate models. Results from the greenhouse experiment showed a statistically significant (p

2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) is one of the earliest myelin-related proteins to be specifically expressed in differentiating oligodendrocytes (ODCs) in the central nervous system (CNS) and is implicated in myelin biogenesis. CNP possesses an in vitro enzymatic activity, whose in vivo relevance remains to be defined, because substrates with 2',3,-cyclic termini have not yet been identified. To characterize CNP function better, we previously determined the structure of the CNP catalytic domain by NMR. Interestingly, the structure is remarkably similar to the plant cyclic nucleotide phosphodiesterase (CPDase) from A. thaliana and the bacterial 2'-5' RNA ligase from T. thermophilus, which are known to play roles in RNA metabolism. Here we show that CNP is an RNA-binding protein. Furthermore, by using precipitation analyses, we demonstrate that CNP associates with poly(A)(+) mRNAs in vivo and suppresses translation in vitro in a dose-dependent manner. With SELEX, we isolated RNA aptamers that can suppress the inhibitory effect of CNP on translation. We also demonstrate that CNP1 can bridge an association between tubulin and RNA. These results suggest that CNP1 may regulate expression of mRNAs in ODCs of the CNS.

Cycloheximide and congeners as inhibitors of eukaryotic protein synthesis from endophytic actinomycetes Streptomyces sps. YIM56132 and YIM56141