Biology subjects

Schuy, C.

Publications and source records attributed to Schuy, C..

4 recordsLinked to original sources

bioRxiv2026

BAP1 loss impairs Non-Homologous End Joining DNA repair promoting genomic instability

The tumor suppressor BRCA1-associated protein 1 (BAP1) is frequently mutated in uveal melanoma, where its loss is associated with poor prognosis. Although BAP1 has been implicated in homologous recombination (HR), its role in non-homologous end-joining (NHEJ) remains poorly defined. Here, we show that BAP1 functions as a central regulator of DNA double-strand break (DSB) repair by coordinating HR and NHEJ. BAP1 depletion disrupts recruitment and activity of the NHEJ machinery. Mechanistically, this defect is driven by aberrant accumulation of H2AK119-ub at DSB sites, promoting excessive DNA end resection and suppressing NHEJ activation. Importantly, inhibition of DNA end resection or suppression of H2AK119-ub restores NHEJ factor recruitment, establishing a causal link between BAP1-regulated histone modifications and repair pathway choice. Clinically, BAP1 loss correlates with genomic instability, providing a mechanistic basis for its association with poor outcomes in uveal melanoma. Collectively, these findings identify BAP1 as a gatekeeper of DSB repair fidelity, revealing a previously unrecognized role in safeguarding NHEJ and maintaining balanced DNA repair.

cancer biology↗

bioRxiv2024

Evaluating plant growth-defence trade-offs by modelling the interaction between primary and secondary metabolism

Understanding the molecular mechanisms behind plant response to stress can enhance breeding strategies and help us design crop varieties with improved stress tolerance, yield and quality. To investigate resource redistribution from growth-to defence-related processes in an essential tuber crop, potato, here we generate a large-scale compartmentalised genome-scale metabolic model, Potato-GEM. Apart from a large-scale reconstruction of primary metabolism, the model includes the full known potato secondary metabolism, spanning over 600 reactions that facilitate the biosynthesis of 182 distinct potato secondary metabolites. Constraint-based modelling identifies that the activation of the largest amount of secondary (defence) pathways occurs at a decrease of the relative growth rate of potato leaf, due to the costs incurred by defence. We then obtain transcriptomics data from experiments exposing potato leaves to two biotic stress scenarios, a herbivore and a viral pathogen, and apply it as constraints to produce condition-specific models. We show that these models recapitulate experimentally observed decreases in relative growth rates under treatment, enabling us to pinpoint the metabolic rewiring underlying growth-defence trade-offs. Potato-GEM thus presents a useful resource to study and broaden our understanding of potato and general plant defence responses under stress conditions.

systems biology↗

bioRxiv2024

Integration of multi-omics and deep phenotyping provides novel insights into multiple abiotic stress responses in potato

Potato is highly water and space efficient but susceptible to abiotic stresses such as heat, drought, or flooding, which are severely exacerbated by climate change. Understanding of crop acclimation to abiotic stress, however, remains limited. Here, we present a comprehensive molecular and physiological high-throughput profiling of potato (Solanum tuberosum, cv. Desiree) under heat, drought and waterlogging applied as single stresses or in combinations designed to mimic realistic future scenarios. Stress-responses were monitored via daily phenotyping and multi-omics analyses of leaf samples comprising transcriptomics, proteomics, metabolomics and hormonomics at several timepoints during and after stress treatments. Additionally, critical metabolites of tuber samples were analysed at the end of the stress period. Integrative analysis of multi-omics data was performed using a bioinformatic pipeline, which was established here, based on machine learning and knowledge networks. Overall, waterlogging had the most immediate and dramatic effects on potato plants, interestingly activating ABA-responses similar to drought stress. In addition, we observed distinct stress signatures at multiple molecular levels in response to heat or drought and to a combination of both. In response to all treatments, we found a downregulation of photosynthesis at different molecular levels, an accumulation of minor amino acids and diverse stress induced hormones. Our integrative multi-omics analysis provides global insights into plant stress responses, facilitating improved breeding strategies towards climate-adapted potato varieties. One Sentence SummaryIntegrated multi-omics analysis of high-throughput phenotyping in potato reveals distinct molecular signatures of acclimation to single and combined abiotic stresses related to climate change.

plant biology↗

bioRxiv2024

FLASH Bragg-peak irradiation with a therapeutic carbon ion beam: first in vivo results

Background and purposeIn recent years, ultra-high dose rate (UHDR) irradiation has emerged as a promising innovative approach to cancer treatment. Characteristic feature of this regimen, commonly referred to as FLASH effect, demonstrated primarily for electrons, photons or protons, is the improved normal tissue sparing, while the tumor control is similar to the one of the conventional dose-rate (CDR) treatments. The FLASH mechanism is, however, unknown. One major question is whether this effect is maintained when using densely ionizing (high-LET) heavy nuclei. Materials and MethodsHere we report the effects of 20 Gy UHDR heavy ion irradiation in clinically relevant conditions, i.e., at high-LET in the spread-out Bragg peak (SOBP) of a 12C beam using an osteosarcoma mouse model. ResultsWe show that UHDR irradiation was less toxic in the normal tissue compared to CDR while maintaining tumor control. The immune activation was also comparable in UHDR and CDR groups. We observed that the gut microbiome was altered in mice injected with the tumor compared to healthy animals, but both UHDR and CDR exposures steered the metagenome toward a balanced state. ConclusionsThe results show that the FLASH effect is safe and effective in heavy ion therapy and provide an important benchmark for the current mechanistic FLASH models. Highlights- FLASH irradiation with SOBP carbon ions spares normal tissue in mouse - Tumor control, immune response, and gut microbioma changes are induced at the same extent both at conventional and ultra-high dose rate - FLASH carbon ion irradiation is a safe and effective alternative to conventional radiotherapy.

cancer biology↗