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SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO
Abstract Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach1–3. Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO, for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37 (also known as SKIC3), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD.
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Widespread occurrence and relevance of phosphate storage in foraminifera
Abstract Foraminifera are ubiquitous marine protists that intracellularly accumulate phosphate1, an important macronutrient in marine ecosystems and in fertilizer potentially leaked into the ocean. Intracellular phosphate concentrations can be 100–1,000 times higher than in the surrounding water1. Here we show that phosphate storage in foraminifera is widespread, from tidal flats to the deep sea. The total amount of intracellular phosphate stored in the benthic foraminifer Ammonia confertitesta in the Wadden Sea during a bloom is as high as around 5% of the annual consumption of phosphorus (P) fertilizer in Germany. Budget calculations for the Southern North Sea and the Peruvian Oxygen Minimum Zone indicate that benthic foraminifera may buffer riverine P runoff for approximately 37 days at the Southern North Sea and for about 21 days at the Peruvian margin. This indicates that these organisms are probably relevant for marine P cycling—they potentially buffer anthropogenic eutrophication in coastal environments. Phosphate is stored as polyphosphate in cell organelles that are potentially acidocalcisomes. Their metabolic functions can range from regulation of osmotic pressure and intracellular pH to calcium and energy storage. In addition, storage of energetic P compounds, such as creatine phosphate and polyphosphate, is probably an adaptation of foraminifera to O2 depletion.