In the sacred cell walls, conflict simmers; a tenuous peace, and perhaps its very survival, rests on the thinnest of margins. Housed in the cell’s internal sanctuary – the nucleus – is its most precious possession, the code that guides each of its actions: DNA. Safeguarding the fidelity of this code is paramount, because even small disturbances can wreak havoc on critical functions or, even worse, engender a plague that threatens not only the cell but the entire body in which it resides. But in its struggle for survival, the cell is faced with a cruel irony: to support its vital functions, it must foster within its walls chemical agents that would pervert its genetic material at any opportunity. Much of the protective role of DNA lies with the nuclear membrane, a closed wall that carefully controls those to which it gives access. Even so, the specter of disaster is still present; the nuclear membrane can rupture, causing the spillage of DNA, an influx of toxic agents and a desperate rush to repair the breach and stem the damage.
A nucleus, fortunately, ruptures relatively rarely and can usually be repaired quickly. A micronucleus, on the other hand, is not so fortunate. Micronuclei (MN) form when a chromosome separates from the pack during mitosis, resulting in the construction of a secondary nuclear membrane around this isolated DNA. MNs are subject to irreparable breakdown, leaving their DNA at particular risk for major mutagenic events. “Despite the high frequency of MN disruption and its potential to radically change gene expression, the molecular mechanisms of membrane disruption in MN and its full consequences are unclear,” writes the group led by Dr. Emily Hatch, Assistant Professor of Fundamental Sciences at Fred Hutch. Division and member of the Fred Hutch / UW Cancer Consortium. In a new article by Life Sciences Alliance Led by Hatch Lab postdoctoral fellow Dr Anna Mammel, the group identifies new features that influence membrane stability in ND.
The rupture is in part caused by defects in the nuclear lamina, a cytoskeletal network that lines the inner surface of the nuclear membrane, writes the group: rupture of membranes. But the rupture can be very variable, some MN being more prone to it than others. Considering this fact, the authors felt that a major feature that distinguishes the different micronuclei is the chromosome they contain. So the group used a Fluorescent In situ Hybridization approach (FISH) to identify chromosomes in specific micronuclei and determine if there was a match between micronucleus disruption and chromosomal identity. While most of the micronuclei eventually ruptured, they found that chromosome identity was a reliable predictor of how quickly disruption occurs – micronuclei containing chromosome 18, for example, ruptured very quickly, while that those containing chromosome 19 exhibited a significantly delayed rupture, indicating a more stable condition.
The authors then examined several properties that differ between chromosomes – length, gene density, presence of ribosomal DNA, size and position of centromeres – to determine which properties promote MN stability. They found two of these traits: the length of chromosomes and the density of genes. Why could these two traits confer stability? Regarding chromosome length, the authors postulate that larger micronuclei may be inherently more stable, possibly due to an increased ability to recruit nuclear proteins. Indeed, they found that micronuclei containing more than one chromosome were also more stable and that the larger micronuclei contained more of the nuclear blade protein Lamin B1 and the nuclear pore complex protein Nup133 and had less lacunae in the core. nuclear blade. The influence of gene density on MN stability was less clear – it did not appear to be due to increased MN size, nor did these MNs exhibit an increased ability to recruit nuclear proteins. However, while the small MNs containing gene-dense chromosomes had very little Lamin B1, they seemed to make very good use of what they had – the architecture of the lamina, assessed by superresolution microscopy, appeared to be well organized. with few gaps. Thus, the authors concluded that gene-rich chromosomes can, via a still unknown mechanism, promote more stable nuclear lamina organization in micronuclei than gene-poor chromosomes.