Biology subjects

Islam, R. A.

Publications and source records attributed to Islam, R. A..

4 recordsLinked to original sources

bioRxiv2026

Pharmacological stress exposes hidden allelic background effects in genetic interaction screen normalisation

Synthetic Genetic Array (SGA) analysis comprises the high-throughput crossing of a query deletion strain against a genome-wide deletion library to score fitness interactions in thousands of double mutants. SGAs have produced comprehensive genetic interaction maps in yeasts and have emerged as a leading platform for pharmacogenomics: mapping genetic modifiers of drug response, identifying synthetic lethal targets and illuminating mechanisms of drug action and resistance. We have previously demonstrated that in fission yeast, the ade6 mutant is functionally neutral relative to the parental library and can serve as a standard negative control for SGA screens. Here, while we confirm our previous observation, we show that this neutrality fails under pharmacological stress. Using Torin1, an ATP-competitive TOR kinase inhibitor, we demonstrate that the ade6 SGA fitness profile diverges from that of the parental library in a dose-dependent and genomically widespread manner. At 2 M Torin1 only 12.2% of scored genes exceed a 1.5-fold fitness difference between backgrounds; at 3 M this proportion rises to 43.2% -a 3.5-fold increase driven by qualitative reorganisation of the genetic interaction landscape rather than simple scaling of pre-existing differences. Gene ontology analysis of divergent genes implicates autophagy, iron starvation responses, central carbon metabolism, and vesicle trafficking, consistent with TOR-regulated nutrient adaptation being differentially affected by the ade6-M210/M216 point mutations in the library versus the ade6 null in the SGA control. Our results have implications in fission yeast and beyond and we propose solutions towards reliable retrieval of genetic interactions.

genetics↗

bioRxiv2026

Bro1-Mediated Trafficking Couples TOR Signalling to Cellular Metabolism and Longevity

Adaptation to nutrient availability requires coordination between growth control, metabolism, and intracellular trafficking. In eukaryotes, inhibition of Target of Rapamycin (TOR) signalling robustly promotes stress resistance and longevity, yet how reduced growth signalling is coupled to organelle dynamics and proteome remodelling remains unclear. Here, we identify the conserved ESCRT-associated protein Bro1 as a central integrator of TOR signalling, vacuolar trafficking, and metabolic adaptation. Using fission yeast, we show that Bro1 is required for normal lifespan and for the global proteomic reprogramming that accompanies TOR inhibition. In Bro1 mutant cells, repression of ribosome biogenesis is uncoupled from activation of catabolic, vacuolar, and metabolic pathways, resulting in an altered metabolic state characterised by elevated lipid metabolism and increased abundance of nutrient transporters. Mechanistically, Bro1 promotes TOR-dependent cargo deubiquitination, vacuolar trafficking, and turnover of plasma membrane hexose transporters and enables appropriate nuclear relocalisation of the transcriptional repressor Scr1. In the absence of Bro1, nutrient transporters persist at the cell surface despite TOR inhibition, conferring resistance to TOR inhibitors while impairing stress responses and reducing lifespan. Together, our findings establish Bro1 as a key coordinator linking ESCRT-mediated endosomal-vacuolar trafficking to TOR-dependent metabolic control. By coupling growth suppression to enhanced recycling and cellular maintenance, Bro1 enables the transition from growth to longevity-promoting states, revealing a mechanism connecting intracellular trafficking, metabolism, and ageing.

genetics↗

bioRxiv2025

Compromised ESCRT signalling is sufficient for resistance to the Target of Rapamycin Complex inhibitor Torin1 in fission yeast

BackgroundFission yeast cells defective in Golgi-endosomal sorting display high resistance to Torin1, a pan-Target of Rapamycin (TOR) inhibitor. TOR complexes regulate the ESCRT system to integrate nutrient availability with cell division. TOR activity is frequently deregulated in cancer, making it an attractive therapeutic target. Deregulated ESCRT activity has also been associated with cancer, but its role in mediating drug resistance is not fully understood. Herein, we have investigated the role of the ESCRT system in regulating sensitivity to Torin1. MethodsGrowth assays were used to monitor the growth of yeast cells. The effect of Torin1 on protein expression was monitored by immunoblotting. Fluorescence microscopy was used to investigate the action of Torin1 on protein localization. ResultsThe ESCRT system mediates Torin1-induced degradation of amino acid and glucose transporters. The expression of these transporters at the plasma membrane is not abolished in ESCRT mutants. Mutants unable to effectively ubiquitylate these transporters are also resistant to Torin1. Impaired ESCRT-mediated protein degradation is associated with strong resistance to Torin1. ConclusionsMutations in genes encoding ESCRT components have been reported in cancer. We present evidence that compromised ESCRT signalling is sufficient for resistance to Torin1. Cells defective in ESCRT signalling or ubiquitin homeostasis are highly resistant to Torin1. Our studies demonstrate that defective ESCRT-mediated proteolysis can suppress sensitivity to Torin1.

cell biology↗

bioRxiv2025

A Time-Resolved High-Throughput Screening of Fission Yeast Deletion Mutants for Oxidative Stress Resistance

Cells typically balance growth with stress responses - growing rapidly in low stress conditions and halting growth to defend against stress or to repair stress-induced damage. While numerous genome-wide screens have identified mutants resistant to oxidative stress, these have largely relied on static, end-point measurements. Here, we take a dynamic, time-resolved approach to uncover how fission yeast, Schizosaccharomyces pombe, adapts to oxidative stress over time. We have tracked the growth of 3,420 deletion mutants across nine time points spanning four days on both nutrient-rich solid media and that containing oxidative stress induced by hydrogen peroxide. This kinetic strategy revealed not just resistant or sensitive mutants. It allowed clustering of growth patterns across time and uncovered mutants that are capable of transiently uncoupling growth from stress response. Hydrogen peroxide induced a dose-dependent delay in colony expansion in most deletion strains, yet 15 mutants consistently maintained robust growth. These belong to different functional categories, highlighting diverse potential mechanisms ranging from altered DNA damage checkpoints to metabolic rewiring and growth regulation. By capturing dynamic trajectories rather than static outcomes, this study exposes hidden layers of growth under oxidative stress and identifies new genetic determinants of cellular resilience in fission yeast.

cell biology↗