RNA deadenylation complexes in development and diseases.

RNA deadenylation, the process of shortening of the 3' poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts. Such regulation influences cell growth, proliferation, and differentiation at the cellular level; and contributes to establish polarity and regulate signaling at the tissue level. Dysregulation of deadenylation processes have also been implicated in human diseases ranging from cardiac diseases and neurodevelopmental disorders to cancers. In this review, we will discuss mechanisms of gene expression control mediated by the RNA deadenylation complexes and highlight relevant evidence supporting the emerging roles of RNA deadenylation and its regulatory proteins during development and in diseases. A systemic understanding of these mechanisms will be a critical foundation for development of effective strategies to therapeutically target them.

Screen-Printed Sensors for Colorimetric Detection of Hydrogen Sulfide in Ambient Air.

A fast and sensitive method to monitor hydrogen sulfide (H2S) in ambient air based on a visible color change of a printed disposable sensor has been developed. As gas-sensitive material, an immobilized copper(II) complex of the azo dye 1-(2-pyridylazo)-2-naphtol (H-PAN) was synthesized and prepared in an ethyl cellulose matrix for screen printing. If H2S is present in ambient air, the gas sensitive layer changes its color from purple to yellow. A pre-primed polyethylene (PE) foil and a coated offset paper served as the printing substrate. The colorimetric response to the target gas was measured by UV/Vis spectroscopy in reflection at H2S concentrations between 1 to 20 ppm. Possible cross-sensitivities of the printed sensors towards methane (CH4), formaldehyde (CH2O), carbon monoxide (CO), ammonia (NH3), and nitrogen dioxide (NO2), as well as the long-term stability was investigated. Furthermore, reflection measurements of the Cu-PAN complex on an amorphous silica powder under gas admission served as preliminary test for the subsequent paste development.

Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets.

A hallmark of all primary and metastatic tumours is their high rate of glucose uptake and glycolysis. A consequence of the glycolytic phenotype is the accumulation of metabolic acid; hence, tumour cells experience considerable intracellular acid stress. To compensate, tumour cells upregulate acid pumps, which expel the metabolic acid into the surrounding tumour environment, resulting in alkalization of intracellular pH and acidification of the tumour microenvironment. Nevertheless, we have only a limited understanding of the consequences of altered intracellular pH on cell physiology, or of the genes and pathways that respond to metabolic acid stress. We have used yeast as a genetic model for metabolic acid stress with the rationale that the metabolic changes that occur in cancer that lead to intracellular acid stress are likely fundamental. Using a quantitative systems biology approach we identified 129 genes required for optimal growth under conditions of metabolic acid stress. We identified six highly conserved protein complexes with functions related to oxidative phosphorylation (mitochondrial respiratory chain complex III and IV), mitochondrial tRNA biosynthesis [glutamyl-tRNA(Gln) amidotransferase complex], histone methylation (Set1C-COMPASS), lysosome biogenesis (AP-3 adapter complex), and mRNA processing and P-body formation (PAN complex). We tested roles for two of these, AP-3 adapter complex and PAN deadenylase complex, in resistance to acid stress using a myeloid leukaemia-derived human cell line that we determined to be acid stress resistant. Loss of either complex inhibited growth of Hap1 cells at neutral pH and caused sensitivity to acid stress, indicating that AP-3 and PAN complexes are promising new targets in the treatment of cancer. Additionally, our data suggests that tumours may be genetically sensitized to acid stress and hence susceptible to acid stress-directed therapies, as many tumours accumulate mutations in mitochondrial respiratory chain complexes required for their proliferation.