Biology subjects

Mathavarajah, S.

Publications and source records attributed to Mathavarajah, S..

5 recordsLinked to original sources

bioRxiv2026

Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit

Rhabdomyosarcoma (RMS) is a multi-subtype, high-risk pediatric sarcoma with a low mutational burden. The mutations found in RMS often alter genes involved in transcriptional control. Approaches to target dysregulated RMS transcription have remained elusive. Here, we develop a novel approach to target RMS transcription comprising simultaneous targeting of two distinctly acting transcriptional co-activators. We discover a common identity-controlling pan-RMS core regulatory circuit (CRC) composed of oncogenic and lineage-specific myogenic master transcription factors (mTFs). Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent inhibitor of the pan-RMS CRC, though with efficacy-limiting toxicities. To enhance efficacy, we identify the mTF-binding co-activator EYA2 as a co-factor of this pan-RMS CRC and exploit a new second-generation EYA1/2 inhibitor, LG1-34, to disrupt its function. Combined co-activator inhibition inactivates the CRC and synergistically reduces RMS growth. This strategy dually targets CRC-associated co-activators to cooperatively suppress the RMS transcriptome and enforce cell death.

cancer biology↗

bioRxiv2024

The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy

The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report the first knockout model for PRP4K in the social amoeba Dictyostelium discoideum, revealing a new function in splicing events controlling autophagy. When prp4k knockout amoebae underwent multicellular development, we observed defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion was found to be impaired after PRP4K loss in both human cell lines and amoebae. Mechanistically, PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restored normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a novel PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution.

cell biology↗

bioRxiv2022

PML and PML-like exonucleases restrict retrotransposons in jawed vertebrates

We have uncovered a novel role for the promyelocytic leukemia (PML) gene and novel PML-like DEDDh exonucleases in the maintenance of genome stability through the restriction of LINE-1 (L1) retrotransposition in jawed vertebrates. Although the PML tumour suppressor protein in mammals is SUMOylated and forms nuclear bodies, we found that the spotted gar PML ortholog and related proteins in fish are not SUMOylated and function as cytoplasmic DEDDh exonucleases. In contrast, more closely related avian and turtle PML proteins are predicted to be SUMOylated and localized both to the cytoplasm and to nuclear bodies. We also identified PML-like exon 9 (Plex9) genes in teleost fishes that encode exonucleases sharing homology to gar PML. In an example of convergent evolution and akin to TREX1, gar PML and zebrafish Plex9 proteins suppressed L1 retrotransposition and could complement TREX1 knockout in mammalian cells. We also characterized the first non-mammalian TREX1 homologs in axolotl. Following export to the cytoplasm, the human PML-I isoform also restricted L1 through its conserved C-terminus and suppressed CGAS activation. Thus, PML first emerged as a cytoplasmic suppressor of retroelements, and this function is retained in amniotes despite its role in the assembly of nuclear bodies and the acquisition of SUMO-modification.

molecular biology↗

bioRxiv2020

Pandemic danger to the deep: the risk of marine mammals contracting SARS-CoV-2 from wastewater

We are in unprecedented times with the ongoing COVID-19 pandemic. The pandemic has impacted public health, the economy and our society on a global scale. In addition, the impacts of COVID-19 permeate into our environment and wildlife as well. Here, we discuss the essential role of wastewater treatment and management during these times. A consequence of poor wastewater management is the discharge of untreated wastewater carrying infectious SARS-CoV-2 into natural water systems that are home to marine mammals. Here, we predict the susceptibility of marine mammal species using a modelling approach. We identified that many species of whale, dolphin and seal, as well as otters, are predicted to be highly susceptible to infection by the SARS-CoV-2 virus. In addition, geo-mapping highlights how current wastewater management in Alaska may lead to susceptible marine mammal populations being exposed to the virus. Localities such as Cold Bay, Naknek, Dillingham and Palmer may require additional treatment of their wastewater to prevent virus spillover through sewage. Since over half of these susceptibility species are already at risk worldwide, the release of the virus via untreated wastewater could have devastating consequences for their already declining populations. For these reasons, we discuss approaches that can be taken by the public, policymakers and wastewater treatment facilities to reduce the risk of virus spillover in our natural water systems. Thus, we indicate the potential for reverse zoonotic transmission of COVID-19 and its impact on marine wildlife; impacts that can be mitigated with appropriate action to prevent further damage to these vulnerable populations.

ecology↗

bioRxiv2020

PRP4K is a haploinsufficient tumour suppressor negatively regulated during epithelial-to-mesenchymal transition

The pre-mRNA processing factor 4 kinase (PRP4K, also known as PRPF4B) is an essential gene. However, reduced PRP4K expression is associated with aggressive breast and ovarian cancer phenotypes including taxane therapy resistance, increased cell migration and invasion in vitro and cancer metastasis in mice; results consistent with PRP4K being a haploinsufficient tumour suppressor. Increased cell migration and invasion is associated with epithelial-to-mesenchymal transition (EMT), but how reduced PRP4K levels affect normal epithelial cell migration or EMT has not been studied. Depletion of PRP4K by small hairpin RNA (shRNA) in non-transformed mammary epithelial cell lines (MCF10A, HMLE) reduced or had no effect on 2D migration in the scratch assay but resulted in greater invasive potential in 3D transwell assays. Depletion of PRP4K in mesenchymal triple negative breast cancer cells (MDA-MB-231) resulted in both enhanced 2D migration and 3D invasion, with 3D invasion correlated with higher fibronectin levels in both MDA-MB-231 and MCF10A cells and without changes in E-cadherin. Induction of EMT in MCF10A cells, by treatment with WNT-5a and TGF-{beta}1, or depletion of eukaryotic translation initiation factor 3e (eIF3e) by shRNA, resulted in significantly reduced PRP4K expression. Mechanistically, induction of EMT by WNT-5a/TGF-{beta}1 reduced PRP4K transcript levels, whereas eIF3e depletion led to reduced PRP4K translation. Finally, reduced PRP4K levels after eIF3e depletion correlated with increased YAP activity and nuclear localization, both of which are reversed by overexpression of exogenous PRP4K. Thus, PRP4K is a haploinsufficient tumour suppressor negatively regulated by EMT, that when depleted in normal mammary cells can increase cell invasion without inducing full EMT.

cancer biology↗