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EFFECTS OF PROGERIN EXPRESSION AND DEREGULATED NUCLEAR ENVELOPE REFORMATION AFTER MITOTIC CELL DIVISION ON MICRONUCLEAR STABILITY

Allard, Aurore (2025) MOBN02 20242
Degree Projects in Molecular Biology
Popular Abstract
Beyond the main nucleus: the secret lives of micronuclei

Imagine your cells diligently copying their precious genetic blueprint every time they divide. This astonishing process, however, is not foolproof. When errors inevitably creep in, especially under stress like radiation or certain drugs, our cells face a terrifying choice: halt operations and attempt repairs or press on, risking chaos. This chaos, known as genomic instability, is linked to diseases such as cancer and the accelerated march of aging. At the heart of this cellular drama are micronuclei: tiny, often overlooked packets of misplaced or damaged DNA that become separated from the main nucleus during faulty cell division. Their increasing numbers often correlate with a... (More)
Beyond the main nucleus: the secret lives of micronuclei

Imagine your cells diligently copying their precious genetic blueprint every time they divide. This astonishing process, however, is not foolproof. When errors inevitably creep in, especially under stress like radiation or certain drugs, our cells face a terrifying choice: halt operations and attempt repairs or press on, risking chaos. This chaos, known as genomic instability, is linked to diseases such as cancer and the accelerated march of aging. At the heart of this cellular drama are micronuclei: tiny, often overlooked packets of misplaced or damaged DNA that become separated from the main nucleus during faulty cell division. Their increasing numbers often correlate with a tumor's aggressiveness and its resistance to treatment.

But what exactly happens to these micronuclei once they form? Do they simply vanish, or do they re-enter the main nucleus, potentially sowing seeds of further disaster, like the catastrophic chromosomal shattering known as "chromothripsis"? To explore this, I used specialized human bone cancer cells (U-2 OS) engineered to express progerin, a mutant protein causing premature aging in Hutchinson-Gilford progeria syndrome. Progerin disrupts the nuclear envelope, which is the vital membrane that normally keeps our DNA safe and organized, making these cells more vulnerable to damage. Using powerful microscopy techniques, including fluorescence microscopy and live-cell imaging, I discovered that under treatments inducing DNA damage or disrupting cell division, micronuclei were not only more prevalent but also more fragile in progerin-expressing cells. This fragility often led to micronuclear rupture and the release of DNA into the cytoplasm, contributing to genomic instability. This exposed DNA can trigger immune responses or become the site of further genetic damage, both of which are linked to cancer development and age-related diseases.

Even more interesting was what happened over time, especially when we introduced specific stressors such as ATR and MPS1 inhibitors, a diverse set of fates emerged for these rogue DNA packages. Some micronuclei were reincorporated into new nuclei during later cell divisions, like damaged pages being awkwardly glued back into the book, while others persisted or degraded, reflecting how treatment impacted their stability.

Crucially, the proportion of persistent micronuclei decreased significantly under these treatments in both lamin A and progerin-expressing cells, while conversely, the proportion of ruptured micronuclei increased. This indicates that disrupting the cell's ability to manage its nuclear integrity led to more erratic behavior of micronuclei, pushing them toward rupture rather than persistence. Interestingly, the dynamics of micronuclei change significantly based on the stress type and the integrity of the nuclear envelope. This is important because persistent or ruptured micronuclei are thought to contribute to catastrophic events such as chromothripsis, leading to dangerous mutations and tumor formation. The results of my project suggest that a weakened nuclear structure, as seen in progerin-expressing cells or potentially in normal aging, makes this destructive scenario far more likely.

So what's next? Future research could explore whether reinforcing the cell's nuclear envelope reduces the formation or rupture of micronuclei. Such strategies may offer new avenues for addressing genomic instability in aging cells and, in the long run, may even enhance cancer therapies by limiting further genetic damage.

Master’s Degree Project in Molecular Biology, 45 credits, 2025
Department of Biology, Lund University

Supervisor: Matthias Altmeyer and Merula Stout (DMMD, UZH, Switzerland) (Less)
Please use this url to cite or link to this publication:
author
Allard, Aurore
supervisor
organization
course
MOBN02 20242
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9213090
date added to LUP
2025-09-24 14:07:01
date last changed
2025-09-24 14:07:01
@misc{9213090,
  author       = {{Allard, Aurore}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{EFFECTS OF PROGERIN EXPRESSION AND DEREGULATED NUCLEAR ENVELOPE REFORMATION AFTER MITOTIC CELL DIVISION ON MICRONUCLEAR STABILITY}},
  year         = {{2025}},
}