Biology subjects

Sen, O.

Publications and source records attributed to Sen, O..

5 recordsLinked to original sources

bioRxiv2026

Epithelial-Mesenchymal Transition Induces FAM134A-mediated ER-phagy to Regulate Procollagen Secretion

EMT is accompanied by extensive remodeling of the secretory pathway, yet how cancer cells maintain endoplasmic reticulum (ER) homeostasis during this transition remains unclear. Here we show that EMT activates ER-phagy as an adaptive mechanism to constrain secretory output. A genome-wide CRISPR activation screen unexpectedly identified EMT- and MET-associated transcription factors as opposing regulators of ER-phagy, and TGF{beta}-induced EMT robustly stimulated this pathway. Proteomic analysis revealed that ER-phagy regulates EMT-induced secretory protein degradation, including procollagens. Among FAM134 ER-phagy receptors, FAM134A uniquely mediated procollagen degradation through a non-canonical, LC3-independent mechanism. Loss of FAM134A diverted procollagen from degradation to secretion, resulting in a pro-invasive secretome, as conditioned media from FAM134A-deficient cells enhanced matrix invasion. These findings identify ER-phagy as a regulatory node that buffers EMT-associated secretory remodeling and reveal FAM134A as a context-specific suppressor of pro-invasive secretion.

cell biology↗

bioRxiv2026

Biochemical mechanism of p-cresol removal by Thauera aminoaromatica S2

Protein-bound uremic toxins are inefficiently cleared by dialysis and contribute to complications in chronic kidney disease, motivating approaches that target their gut-derived precursors. Here we investigate anaerobic p-cresol metabolism by the environmental denitrifier Thauera aminoaromatica S2, a pathway originally evolved for aromatic pollutant degradation. Proteomic stable isotope probing with 13C-labeled p-cresol reveals strong incorporation of labeled carbon into T. aminoaromatica proteins, whereas parallel incubations with human fecal microbiomes show minimal incorporation, indicating limited intrinsic gut capacity for p-cresol utilization. Label-enriched proteins enable reconstruction of the anaerobic p-cresol degradation pathway and identification of key enzymes synthesized during growth on p-cresol. Moreover, hydrogel-encapsulated T. aminoaromatica remains active during co-incubation with the gut microbiome, achieving complete removal of 0.3 mM p-cresol in less than 10 hours, a timescale compatible with typical intestinal transit in the colon. Together, these findings establish a biochemical basis for repurposing environmental aromatic degradation pathways for gut-localized p-cresol removal.

bioengineering↗

bioRxiv2021

Computational modelling and near-complete kinetochore tracking reveal how chromosome dynamics during cell division are co-ordinated in space and time

Mitotic chromosome segregation is a self-organising process that achieves high fidelity separation of 46 duplicated chromosomes into two daughter cells. Chromosomes must be captured by the microtubule-based spindle, aligned at the spindle equator where they undergo oscillatory motion (metaphase) and then pulled to opposite spindle poles (anaphase). These large and small-scale chromosome movements are driven by kinetochores, multi-protein machines, that link chromosomes to microtubules and generate directional forces. Through automated near-complete tracking of kinetochores at fine spatio-temporal resolution over long timescales, we produce a detailed atlas of kinetochore dynamics throughout metaphase and anaphase in human cells. We develop a hierarchical biophysical model of kinetochore dynamics and fit this model to 4D lattice light sheet experimental data using Bayesian inference. We demonstrate that location in the metaphase plate is the largest factor in the variation in kinetochore dynamics, exceeding the variation between cells, whilst within the spindle there is local spatio-temporal coordination between neighbouring kinetochores of directional switching events, kinetochore-fibre (K-fibre) polymerization/depolymerization state and the segregation of chromosomes. Thus, metaphase oscillations are robust to variation in the mechanical forces throughout the spindle, whilst the spindle environment couples kinetochore dynamics across the plate. Our methods provide a framework for detailed quantification of chromosome dynamics during mitosis in human cells.

cell biology↗

bioRxiv2021

Microtubule-based mitotic spindles contain a micron-sized mixed-nucleotide zone

Current models infer that the microtubule-based mitotic spindle is built from GDP-tubulin with small GTP caps at microtubule plus-ends, including those that attach to kinetochores (K-fibres). Here we reveal that K-fibres additionally contain a dynamic mixed-nucleotide zone that reaches several microns in length. This zone becomes visible in cells expressing fluorescently labelled EBs, a known marker for GTP-tubulin, and endogenously-labelled HURP - a protein which we show to preferentially bind the GDP microtubule lattice in vitro. In living cells HURP accumulates on the ends of depolymerising K-fibres, whilst avoiding recruitment to nascent polymerising K-fibres. This gives rise to a growing "HURP-gap" which we can recapitulate in a minimal computational simulation. We therefore postulate that the K-fibre lattice contains a dynamic, micron-sized mixed-nucleotide zone. One Sentence SummaryWe reveal that the microtubules of the mitotic spindle contain a third, uncharacterized domain, a mixed nucleotide zone that resides between the GTP-cap and the GDP-tubulin lattice.

cell biology↗

bioRxiv2021

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Chromosome mis-segregation during mitosis leads to daughter cells with deviant karyotypes (aneuploidy) and an increased mutational burden through chromothripsis of mis-segregated chromosomes. The rate of mis-segregation and the aneuploidy state are hallmarks of cancer and linked to cancer genome evolution. Errors can manifest as "lagging chromosomes" in anaphase, although the mechanistic origins and likelihood of correction are incompletely understood. Here we combine lattice light sheet microscopy, endogenous protein labelling and computational analysis to define the life history of > 104 kinetochores throughout metaphase and anaphase from over 200 cells. By defining the "laziness" of kinetochores in anaphase, we reveal that chromosomes are at a considerable and continual risk of mis-segregation. We show that the majority of kinetochores are corrected rapidly in early anaphase through an Aurora B dependent process. Moreover, quantitative analyses of the kinetochore life histories reveal a unique dynamic signature of metaphase kinetochore oscillations that forecasts their fate in the subsequent anaphase. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with a new layer of early anaphase error correction required for stable karyotype propagation.

cell biology↗