ETH Zurich

A crucial factor governing the habitability of exoplanets is the availability of bioessential elements such as nitrogen (N) and phosphorous (P), which foster prebiotic chemistry and sustain life after its emergence. However, concentrations of P and N in planetary mantles vary, owing to initial availability and oxidation conditions during planet formation, and thus their characterization and availability in planetary environments are challenging. Here we use a core-formation model to show that moderate oxygen fugacity during core formation is the key parameter to the availability of these two elements, with the existence of a narrow ‘chemical Goldilocks zone’ that allows both P and N to be present with the right abundances in the mantle. Earth falls within this zone, whereas planets with more reducing/oxidizing conditions will sequester P/N into the core, hindering their availability for life. Future observations refining estimates of the oxygen fugacity prevalent during exoplanet core formation will be crucial to properly evaluate exoplanetary habitability and correctly interpret possible biosignatures.

FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Treg cells). Although mice exclusively express FOXP3 in Treg cells, stimulated conventional CD4⁺ T cells (Tconv cells) also transiently express FOXP3 in humans. Mechanisms governing these distinct expression patterns need elucidation. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Treg and Tconv cells to identify cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv cell FOXP3 expression depended on a subset of Treg cell CREs, as well as Tconv-cell-selective positive (NS+) and negative (NS−) CREs. Combinatorial silencing of Tconv cell CREs revealed their epistatic logic. These CREs are occupied and regulated by TFs that we identified as FOXP3 regulators. Finally, mutagenesis of murine NS− CRE revealed its essentiality for restricting FOXP3 expression to Treg cells. We map CRE and TF circuitry to reveal distinct cell- and species-specific regulation of FOXP3 expression.

Recent JWST observations of the temperate sub-Neptune K2-18 b with NIRISS SOSS/NIRSpec G395H and MIRI LRS have yielded apparently inconsistent results: the MIRI spectra exhibit spectral features nearly twice as large as those seen at shorter wavelengths, challenging the high-metallicity, CH₄-rich nonequilibrium model that fits the NIRISS/NIRSpec data. We performed a suite of atmospheric retrievals on both datasets, including free-chemistry, nonequilibrium, and aerosol models, using laboratory-derived complex refractive indices for a variety of photochemical haze analogs. Free retrievals systematically output lower metallicities than inferred by self-consistent chemical disequilibrium models, and the inclusion of absorbing aerosols, especially CH₄-dominated, nitrogen-poor tholins, can further reduce the inferred metallicity by over an order of magnitude. These hazes reproduce the observed NIRISS slope through scattering and match MIRI features via C–H bending absorption near 7 μm, while yielding particle properties consistent with photochemical production in H₂-rich atmospheres. Although their inclusion improves the joint fit and reduces tension between datasets, it also significantly lowers the retrieved CH₄ abundance, highlighting degeneracies between metallicity, composition, and aerosol properties. Our results underscore the importance of aerosol absorption in interpreting temperate sub-Neptune spectra and motivate future JWST observations and laboratory work to break these degeneracies.

Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between WEE1 small-molecule inhibitors and defects in mRNA translation, mediated by activation of the integrated stress response (ISR) through the kinase GCN2. Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775. We demonstrate that this synergy depends on ISR activation, which is induced by the off-target activity of WEE1 inhibitors. Furthermore, PROTAC-based WEE1 inhibitors and molecular glues show reduced or no ISR activation, suggesting potential strategies to minimise off-target toxicity. Our findings reveal that certain WEE1 inhibitors elicit dual toxicity via ISR activation and genotoxic stress, with ISR activation being independent of WEE1 itself or cell-cycle status. This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors.

Base editors create precise genomic edits by directing nucleobase deamination or removal without inducing double-stranded DNA breaks. However, a vast chemical space of other DNA modifications remains to be explored for genome editing. Here we harness the bacterial antiphage toxin DarT2 to append ADP-ribosyl moieties to DNA, unlocking distinct editing outcomes in bacteria versus eukaryotes. Fusing an attenuated DarT2 to a Cas9 nickase, we program site-specific ADP-ribosylation of thymines within a target DNA sequence. In tested bacteria, targeting drives homologous recombination, offering flexible and scar-free genome editing without base replacement or counterselection. In tested yeast, plant and human cells, targeting drives substitution of the modified thymine to adenine or a mixture of adenine and cytosine with limited insertions or deletions, offering edits inaccessible to current base editors. Altogether, our approach, called append editing, leverages the addition of chemical moieties to DNA to expand current modalities for precision gene editing.

The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability^1,2. Unravelling the complementary interplay between these pathways remains a challenge^3,4. Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

The origin of life on Earth required a supply of phosphorus (P) for the synthesis of universal biomolecules. Closed lakes may have accumulated high P concentrations on early Earth. However, it is not clear whether prebiotic P uptake in such settings would then have been sustainable. We show that large closed-basin lakes can combine high P concentrations at steady state with extremely high rates of biological productivity. Our case study is Mono Lake in California, which has close to 1 millimolar dissolved P at steady state despite extremely high rates of biological productivity, in contrast to smaller closed basins where life is scarce. Hence, large closed-basin lakes offer an environment where high rates of prebiotic P productivity can plausibly coexist with high steady-state P concentrations. Such lakes should have readily formed on the heavily cratered and volcanically active surface of early Earth.