Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

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SRSF9 mediates oncogenic RNA splicing of SLC37A4 via liquid–liquid phase separation to promote oral cancer progression

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Oral cancer represents a significant proportion of head and neck malignancies, accounting for approximately 3 % all malignant tumors worldwide. Alternative splicing (AS), post-transcriptional regulatory mechanism, is increasingly linked to development. The precise impact AS on oral progression not well understood. Bioinformatics, semi-quantitative RT-PCR, minigene reporter system detect the skipping SLC37A4 exon 7 in cancer. FRAP, live cell immunofluorescence demonstrates that SRSF9 can undergo liquid-liquid phase separation (LLPS). In vivo vitro experiments with subcutaneous graft tumors, CCK8, EdU, transwell, others were used effects its induced SLC37A4-S isoforms phenotype cells. Our investigation revealed multitude aberrant alternative events within tumor tissues, most notably pronounced gene. This anomaly leads production truncated isoform, SLC37A4-S, which associated poor prognosis significantly augments proliferation metastatic potential cells relative wild-type SLC37A4-L. Mechanically, may play role SLC37A4. Furthermore, capable undergoing LLPS, process driven by arginine-serine-rich (RS) domain. Disruption LLPS through use inhibitors or mutants effectively prevents influence Significantly, our research both regulated contribute cisplatin chemotherapy resistance study elucidates mechanism mediates cancer, thereby establishing basis considering as therapeutic targets treatment.

Language: Английский

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Fragile X mental retardation protein modulates translation of proteins with predicted tendencies for liquid-liquid phase separation

Biosystems, Journal Year: 2025, Volume and Issue: unknown, P. 105405 - 105405

Published: Jan. 1, 2025

Language: Английский

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The role of cytosine methylation in regulating the topology and liquid-liquid phase separation of DNA G-quadruplexes

Chemical Science, Journal Year: 2025, Volume and Issue: 16(10), P. 4213 - 4225

Published: Jan. 1, 2025

Aberrant expansion of GGGGCC DNA repeats that form G-quadruplexes (G4) is the main cause amyotrophic lateral sclerosis (ALS). Expanded induce liquid-liquid phase separation (LLPS) through their interaction with cellular proteins. Furthermore, induces cytosine methylation (mC). Previous studies have shown even slight chemical modifications RNAs and proteins can drastically affect LLPS ability, yet relationship between epigenetic like mC remains unexplored. As a model system, we investigated effects on induced by repeat DNAs show for first time suppresses altering topology G4 from being parallel to antiparallel.

Language: Английский

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Mechanistic insights into DXO1 and XRN3: Regulatory roles of RNA stability, transcription, and liquid-liquid phase separation in Arabidopsis thaliana

Plant Science, Journal Year: 2025, Volume and Issue: 353, P. 112413 - 112413

Published: Feb. 3, 2025

Language: Английский

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catGRANULE 2.0: accurate predictions of liquid-liquid phase separating proteins at single amino acid resolution

Genome biology, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 20, 2025

Liquid-liquid phase separation (LLPS) enables the formation of membraneless organelles, essential for cellular organization and implicated in diseases. We introduce catGRANULE 2.0 ROBOT, an algorithm integrating physicochemical properties AlphaFold-derived structural features to predict LLPS at single-amino-acid resolution. The method achieves high performance reliably evaluates mutation effects on propensity, providing detailed predictions how specific mutations enhance or inhibit separation. Supported by experimental validations, including microscopy data, it predicts across diverse organisms compartments, offering valuable insights into mechanisms mutational impacts. tool is freely available https://tools.tartaglialab.com/catgranule2 https://doi.org/10.5281/zenodo.14205831 .

Language: Английский

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Rethinking transcription factor dynamics and transcription regulation in eukaryotes

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: 4

Published: March 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Language: Английский

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Conservation of Putative Liquid–Liquid Phase Separating Proteins in Multiple Drug-Resistant Mycobacterium tuberculosis: Role in Host–Pathogen Interactions?

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

We observed a high proportion of proteins in pathogenic Mycobacterium species that can potentially undergo liquid-liquid phase separation (LLPS) mediated biomolecular condensate formation, compared to nonpathogenic species. These mainly include the PE-PPE and PE-PGRS families have nucleic acid protein-protein binding functions, typical LLPS proteins. also mapped identified M. tuberculosis (M.tb) drug-resistant databases PubMLST TBProfiler, based upon WHO 2023 catalogue resistance-associated mutations. High sequence conservation LLPS-associated various multiple M.tb isolates points their important role virulence host-pathogen interactions during evolution. This analysis provides perspective on protein evaluation pathogenesis offers avenues for future research aimed at developing innovative strategies combat infection.

Language: Английский

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Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: May 5, 2025

Intrinsically disordered proteins (IDPs) and biomolecular condensates are critical for cellular processes physiological functions. Abnormal can cause diseases such as cancer neurodegenerative disorders. IDPs, including intrinsically regions (IDRs), were previously considered undruggable due to their lack of stable binding pockets. However, recent evidence indicates that targeting them influence processes. This review explores current strategies target IDPs condensates, potential improvements, the challenges opportunities in this evolving field.

Language: Английский

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