Many cancer cells have high rates of chromosome missegregation that can result in micronuclei. A chromosome, or a piece of one, that is separated from the main chromosome mass during anaphase will recruit its own NE. This results in an interphase cell with two nuclear compartments: a primary nucleus, which contains the majority of the chromosomes, and a micronucleus, which contains the missegregated chromosome or chromosome fragment. We found that micronuclei have a high probability of NE rupture but fail to repair. This persistent disruption results in nuclear membrane collapse, cessation of nuclear functions, including DNA replication, and, in many cases, massive DNA damage. Thus, micronucelation can result in aneuploidy and increased genome instability, which are linked to cancer development. In addition, DNA damage in micronuclei has recently been linked to chromothripsis, the massive rearrangement of a chromosome in a single event, which has been identified in several cancers. However, causal links between micronucleation and cancer phenotypes have not been established.
It is still unclear why the NE ruptures, although we have identified one important condition. In both primary nuclei and micronuclei, defects in nuclear lamina organization are highly predictive of NE instability. The nuclear lamina is a network of lamin and membrane proteins that assemble on the inner nuclear membrane and determine the shape and flexibility of the NE. Changes in nuclear morphology are often a hallmark of transformed cells and mutations in the lamin proteins cause human genetic diseases, called laminopathies. Our current model is that defects in lamina assembly or maintenance cause holes to form in the lamina network. These bare patches of membrane are then prone to rupture. However lamina gaps are not sufficient for NE rupture, indicating the existence of additional factors that affect NE stability.
Our approach will combine imaging, biochemical, and genomic techniques with cell-based systems to address the following questions:
- What mechanisms drive NE remodeling? Specifically, why does the NE rupture and what are the mechanisms for repair?
- Why does NE assembly around one chromosome versus many chromosomes cause increased NE instability?
- What are the consequences of losing nuclear compartmentalization for the underlying chromatin and cell functions?
- What are the consequences of NE rupture for genome stability, cell proliferation, and cancer development?