Biology subjects

Mirkovic, M.

Publications and source records attributed to Mirkovic, M..

3 recordsLinked to original sources

bioRxiv2024

Dissociation of the nuclear basket triggers chromosome loss in aging yeast

In many organisms, aging is a clear risk factor for chromosome mis-segregation, the main source of aneuploidy. Here, we report that old yeast cells lose chromosomes by partitioning them asymmetrically to their daughter cells together with the pre-existing (old) spindle pole body (SPB, centrosome equivalent in yeast). Strikingly, remodelling of the nuclear pore complex (NPC) and the displacement of its nuclear basket triggered these asymmetric chromosome segregation events. Simultaneously, nuclear basket displacement caused unspliced pre-mRNAs to leak into the cytoplasm. We show that removing the introns of three genes involved in chromosome segregation was sufficient to fully suppress chromosome loss in old cells. Promoting pre-mRNA leakage in young cells also caused asymmetric chromosome partitioning and loss through the same three introns. Therefore, we propose that basket displacement from NPCs and its consequences for pre-mRNA quality control are key triggers of aging phenotypes such as aneuploidy.

cell biology↗

bioRxiv2018

Delayed aneuploidy stress response of neural stem cells impairs adult lifespan in flies

SummaryStudying aneuploidy during organism development has strong limitations, as chronic mitotic perturbations used to generate aneuploidy result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity.\n\nLarvae challenged with aneuploidy hatch into adults with severe motor defects shortening their lifespan. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, complex array of karyotypes and cellular abnormalities. Notably, when other brain cell-lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed, indicating that stemness state confers resistance to aneuploidy. Sparing solely the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult lifespan, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.\n\nHighlightsO_LIReversible depletion of cohesin results in just a round or two of aberrant cell divisions, generating high levels of aneuploidy.\nC_LIO_LILarvae challenged with aneuploidy during development hatch into impaired adults.\nC_LIO_LIFew cell cycles are sufficient for chromosomal instability to emerge from a previously stable aneuploid state.\nC_LIO_LINeural stemness delays aneuploidy stress response.\nC_LIO_LIProtecting only the neural tissue from aneuploidy rescues adult abnormalities and lifespan.\nC_LI

developmental biology↗

bioRxiv2018

Absence of the Spindle Assembly Checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion

Sister chromatid cohesion is essential for faithful mitosis, as premature cohesion loss leads to random chromosome segregation and aneuploidy, resulting in abnormal development. To identify specific conditions capable of restoring defects associated with cohesion loss, we screened for genes whose depletion modulates Drosophila wing development when sister chromatid cohesion is impaired. Cohesion deficiency was induced by knock-down of the acetyltransferase Separation anxiety (San)/Naa50, a cohesin complex stabilizer. Several genes whose function impacts wing development upon cohesion loss were identified. Surprisingly, knockdown of key Spindle Assembly Checkpoint (SAC) proteins, Mad2 and Mps1, suppressed developmental defects associated with San depletion. SAC impairment upon cohesin removal, triggered by San depletion or artificial removal of the cohesin complex, prevented extensive genome shuffling, reduced segregation defects and restored cell survival. This counterintuitive phenotypic suppression was caused by an intrinsic bias for efficient chromosome bi-orientation at mitotic entry, coupled with slow engagement of error-correction reactions. We conclude that mitotic timing determines the severity of defects associated with cohesion deficiency. Therefore, although divisions are still error-prone, SAC inactivation enhances cell survival and tissue homeostasis upon cohesion loss.

cell biology↗