Biology subjects

Drpic, D.

Publications and source records attributed to Drpic, D..

3 recordsLinked to original sources

bioRxiv2026

Inhibition of V-ATPase function drives apoptosis via GCN1/GCN2 kinase signaling

Natural products are a rich source of bioactive molecules that have served both as templates for drug discovery and as tools to uncover fundamental biological processes. While characterizing the pro-apoptotic activity of the cyanobacterial metabolite Nostatin A, we identified vacuolar-type H-ATPase (V-ATPase) as its molecular target and uncovered an unexpected signalling response preceding cell death initiation. V-ATPase inhibition rapidly activates the integrated stress response (ISR) through engagement of the GCN1/GCN2 kinase module, indicative of ribosomal collisions and translational shutdown. This response is conserved across established V-ATPase inhibitors, including bafilomycin A1, but not with compounds disrupting lysosomal function by other means. Mechanistically, V-ATPase inhibition depletes the pro-survival protein MCL-1 resulting in BAX/BAK-dependent mitochondrial apoptosis. Loss of MCL-1 creates a vulnerability that renders cells dependent on co-expressed BCL-2 family proteins, enabling potent synergy with the BH3 mimetics ABT-737 or venetoclax. Taken together, our results reveal a therapeutically exploitable vulnerability in V-ATPase-reliant or MCL-1 dependent cancers.

cell biology↗

bioRxiv2021

A mitotic screen in Indian muntjac cells unveils how Augmin drives kinetochore fiber maturation

Chromosome segregation in mammals relies on the maturation of a thick bundle of kinetochore-attached microtubules known as k-fibers. How k-fibers mature from initial kinetochore-microtubule attachments remains a fundamental question. By combining functional perturbations in Indian muntjac, a placental mammal with the lowest known chromosome number (n=3) and distinctively large kinetochores, with fixed- and subsecond live-cell super-resolution CH-STED nanoscopy, we uncovered the mechanism by which Augmin mediates k-fiber maturation. Augmin promoted kinetochore microtubule turnover by sustaining microtubule formation from kinetochores and poleward flux, regardless of pioneer centrosomal microtubules. Tracking of microtubule growth events within individual k-fibers revealed a wide angular dispersion, consistent with Augmin-mediated branched microtubule nucleation. Augmin depletion reduced the frequency of microtubule growth events within k-fibers and hampered normal repair after acute k-fiber injury by laser microsurgery. Our work underscores the contribution of microtubule formation from kinetochores and Augmin-mediated microtubule amplification for k-fiber maturation and spindle assembly in mammals.

cell biology↗

bioRxiv2018

Chromosome (mis)segregation is biased by kinetochore size

Summary:\n\nAneuploidy, the gain or loss of chromosomes, arises through problems in chromosome segregation during mitosis or meiosis and has been implicated in cancer and developmental abnormalities in humans [1]. Possible routes to aneuploidy include a compromised spindle assembly checkpoint (SAC), cohesion defects, centrosome amplification, as well as improper kinetochore-microtubule attachments [2]. However, none of these established routes takes into account the intrinsic features of the kinetochore - the critical chromosomal interface with spindle microtubules. Kinetochore size and respective microtubule binding capacity varies between different animal and plant species [3-10], among different chromosomes from the same species (including humans) [3, 11-15], and in response to microtubule attachments throughout mitosis [16-18]. How kinetochore size impacts chromosome segregation remains unknown. Addressing this fundamental question in human cells is virtually impossible, because most of the 23 pairs of chromosomes cannot be morphologically distinguished, while detection of 2-3 fold differences in kinetochore size is limited by diffraction and cannot be resolved by conventional light microscopy in living cells. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (n=3), to track individual chromosomes with distinct kinetochore sizes throughout mitosis. We found that chromosomes with larger kinetochores bi-orient more easily and are biased to congress to the equator in a motor-independent manner. However, they are also more prone to establish erroneous merotelic attachments and lag behind during anaphase. Thus, we uncovered an intrinsic kinetochore feature - size - as an important determinant of chromosome segregation fidelity.

cell biology↗