One-third of monogenic inherited diseases result from premature termination codons (PTCs). Readthrough of in-frame PTCs enables synthesis of full-length functional proteins. However, extended variability in the response to readthrough treatment is found among patients, which correlates with the level of nonsense transcripts. Here, we aimed to reveal cellular pathways affecting this inter-patient variability. We show that activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts carrying PTCs. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTCs, correlating with their response. We further found a significant inverse correlation between the UPR and nonsense-mediated mRNA decay (NMD), suggesting a feedback loop between these homeostatic pathways. We uncovered and characterized the mechanism underlying this NMD-UPR feedback loop, which augments both UPR activation and NMD attenuation. Importantly, this feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Altogether, our study demonstrates the importance of the UPR and its regulatory network for genetic diseases caused by PTCs and for cell homeostasis under normal conditions.

Dvorkin G, Manor M, Sibony M, Chefetz B & Rubin B (2012). Effects of long‐term irrigation with reclaimed wastewater on the efficacy and fate of trifloxysulfuron‐sodium in the soil. Weed Research.52, 441–448. Summary Long‐term irrigation with reclaimed wastewater (RWW) is known to affect the physical, chemical and biological properties of the receiving soil. The sulfonylurea herbicide trifloxysulfuron‐sodium (TFX), an acetolactate synthase inhibitor, is stable in the soil for several months and can carry over to rotational crops; however, its activity in RWW‐irrigated soils is much lower. In this study, we monitored the activity/dissipation of TFX applied on RWW‐irrigated soil. High weed infestation in the treated soil in field studies along with a decrease in the soil activity as determined with test plant was observed, suggesting fast dissipation of the herbicidal activity of TFX in the soil. Dose–response curves of Sorghum bicolor to TFX planted in RWW‐ and in fresh water‐irrigated soils showed higher and more significant damage for both shoots and roots with the fresh water‐irrigated soil. Sterilised RWW‐irrigated soil exhibited higher TFX activity versus non‐sterilised soil. This implies that reduction in TFX activity in RWW‐irrigated soil is probably affected by the microbial activity.