Mechanisms of Micronucleus Rupture
Micronuclei form in human cells when chromatin is incorrectly segregated during mitosis, due to changes in spindle organization, loss of centromeres from unrepaired DNA damage, or defects in checkpoint signaling, among other processes, and recruits its own nuclear envelope to form a smaller nucleus in the same cell as another large nucleus. Micronucleation occurs at low levels in healthy tissue and more frequently in conditions defined by chromosome instability, including many solid tumors and laminopathies. A major feature of micronuclei is their high frequency of rupture and extremely limited repair capacity. As a result, most of the micronuclei in cultured cells become ruptured at some point during interphase and the chromatin remains exposed to the cytoplasm until the next cell division. This causes extensive DNA damage followed by increased invasion and inflammatory signaling that can result in massive chromosome rearrangement and hypermutation, called chromothripsis and kataegis, respectively. These changes are thought to be highly beneficial to cancer initiation and evolution.
Our lab recently found that the physical characteristics of the chromatin trapped in the micronucleus have a significant impact on when the membrane ruptures, with potential downstream implications for the type of DNA damage and extent of signaling changes. Our data suggest that there are different rupture mechanisms depending on the size and state, open or closed, of the missegregated chromosome and we are currently pursuing questions into the molecular mechanisms underlying these differences. Recent work in our lab and others has shown that chromosome missegregation and micronucleation is not random, and thus understanding how chromatin content regulates nuclear envelope organization and stability could be a key factor in explaining why certain aneuploidies and chromothripsis locations are characteristic of specific cancers.
Projects
- What are the molecular mechanisms by which high euchromatin content protects micronuclei from rupture?
- What factors determine protein recruitment differences between large and small micronuclei?
- How does the timing of micronucleus rupture impact downstream consequences?
- Is there a correlation between cancer associated enrichment of single chromosome chromothripsis and chromosome specific missegregation in pre-clinical disease models?
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