Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Chemical RNA digestion enables robust RNA-binding site mapping at single amino acid resolution

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. RNA-binding sites (RBSs) can be identified by liquid chromatography and tandem mass spectrometry analyses of the protein-RNA conjugates created by crosslinking, but RBS mapping remains highly challenging due to the complexity of the formed RNA adducts. Here, we introduce RBS-ID, a method that uses hydrofluoride to fully cleave RNA into mono-nucleosides, thereby minimizing the search space to drastically enhance coverage and to reach single amino acid resolution. Moreover, the simple mono-nucleoside adducts offer a confident and quantitative measure of direct RNA-protein interaction. Using RBS-ID, we profiled similar to 2,000 human RBSs and probedStreptococcus pyogenesCas9 to discover residues important for genome editing11sci

Where did all the nitrogen go? Fate of nitrogen inputs to large watersheds in the northeastern U.S.A.

To assess the fate of the large amounts of nitrogen (N) brought into the environment by human activities, we constructed N budgets for sixteen large watersheds (475 to 70,189 km 2) in the northeastern U.S.A. These watersheds are mainly forested (48-87%), but vary widely with respect to land use and population density. We combined published data and empirical and process models to set up a complete N budget for these sixteen watersheds. Atmospheric deposition, fertilizer application, net feed and food inputs, biological fixation, river discharge, wood accumulation and export, changes in soil N, and denitrification losses in the landscape and in rivers were considered for the period 1988 to 1992. For the whole area, on average 3420 kg of N is imported annually per km 2 of land. Atmospheric N deposition, N 2 fixation by plants, and N imported in commercial products (fertilizers, food and feed) contributed to the input in roughly equal contributions. We quantified the fate of these inputs by independent estimates of storage and loss terms, except for denitrification from land, which was estimated from the difference between all inputs and all other storage and loss terms. Of the total storage and losses in the watersheds, about half of the N is lost in gaseous form (51%, largely by denitrification). Additional N is lost in riverine export (20%), in food exports (6%), and in wood exports (5%). Change in storage of N in the watersheds in soil organic matter (9%) and wood (9%) accounts for the remainder of the sinks. The presence of appreciable changes in total N storage on land, which we probably under-rather than overestimated, shows that the N budget is not in steady state, so that drainage and denitrification exports of N may well increase further in the future.SCOPUS: ar.jinfo:eu-repo/semantics/publishe