Athapaththu, A. M. G. K. | bioRxiv Science

bioRxiv2024

Chemical genetics in C. elegans identifies anticancer mycotoxins chaetocin and chetomin as potent inducers of a nuclear metal homeostasis response

C. elegans numr-1/2 (nuclear-localized metal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activates numr-1/2 strongly in the alimentary canal but is distinct from metal exposure because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism in C. elegans as genetic disruption and RNAi screening of homologs did not induce numr-1/2 in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to induce numr-1/2. ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect on numr-1/2, suggesting a dimer requirement. Chetomin inhibits C. elegans growth at low micromolar levels and loss of numr-1/2 increases sensitivity; C. elegans and Chaetomiaceae fungi inhabit similar environments raising the possibility that numr-1/2 functions as a defense mechanism. There is no direct ortholog of numr-1/2 in humans, but RNAseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

pharmacology and toxicology↗

bioRxiv2019

A preliminary investigation on the dependence of arthropod diversity on vegetation diversity across four contrasting ecosystems in Hanthana mountain range of Sri Lanka

Arthropods contribute significantly to biodiversity and vegetation provides a habitat and resources for them to survive, exist and propagate. We report a preliminary investigation on the extent to which arthropod diversity is dependent upon vegetation diversity across different ecosystems in a humid tropical climate. We determined the diversity of arthropods in four ecosystems closely-located ecosystems with different vegetation. Vegetation surrounding an aquatic environment (AQ), a broad-leaved wet, evergreen forest ecosystem (BL), a Pinus caribaea monoculture plantation (PN) and a Pinus plantation artificially enriched with indigenous broad-leaved tree species (PNEN) located in the Hanthana mountain range in Central Sri Lanka were selected. In each environment, arthropods were sampled in three randomly-selected sites (5 m x 5 m) using four sampling methods. Collected arthropods were identified upto the highest possible taxa using standard identification keys. Simultaneously, vegetation diversity was determined via a plant census. Arthropod and vegetation diversities were computed separately for each site using Shannon-Wiener Index (H).\n\nWithin the 300 m2 area of observation plots, arthropod individuals belonging to 68 species and 43 families were found. AQ had the greatest arthropod diversity (H=2.642), dominated by Olios spp. followed by BL (H=2.444), dominated by three arthropods, namely, a tettigonid species, Oxytate spp. and Psechrus spp. PN had the next highest arthropod diversity (H=1.411), dominated by Dicaldispa spp. The lowest arthropod diversity was found at PNEN (H=1.3500), dominated by an ant species. Contrastingly, PNEN had the highest plant diversity (H=2.614) and PN the lowest (H=0.879). AQ (H=1.810) and BL (H=1.871) had intermediate values.\n\nIn a regression involving data from AQ, BL and PN, arthropod diversity was linearly dependent on plant diversity (R2=0.423) whereas it was not so when PNEN was also included (R2=0.008). This finding supports the hypothesis that while higher plant diversity contributes to greater arthropod diversity in ecosystems where human intervention is minimal, artificial enrichment of plant diversity does not necessarily increase arthropod diversity in the short-to medium-term. Further investigations are needed to substantiate these preliminary findings and validate the above hypothesis.

ecology↗