Nuclear integrity and genome stability
Project leader: Coen Campsteijn
The nuclear envelope (NE) constitutes the physical barrier that compartmentalizes the nucleus and protects the genome from damage. However, nuclear compartmentalization is compromised under various conditions, the classical example of which is the open mitosis of many metazoans. More recently, interphase cells were shown to display reversible NE leaks, with increased frequency in cancer cells and cells with defects in their nuclear lamina (laminopathies). In addition, micronuclei arising from chromosome segregation defects were shown to be prone to irreversible rupture of their NE.
We have been aware of transient nuclear envelope ruptures for some time now, and evidence has been accumulating highlighting its association with DNA damage. However, it remains unclear why ruptures happen, what causes the associated DNA damage, and how cells respond to restore compartmentalization. Our recent identification of the ESCRT-III machinery as the first NE repair complex has opened exciting new avenues towards elucidating the molecular framework that controls NE integrity. This will allow us to dissect the importance of NE integrity to chromatin function and genome stability, as well as its contributions to the aetiology of cancer and laminopathies.
Central aim and research questions
The central aim of our lab is to gain in-depth mechanistic and spatiotemporal insight into the processes that control nuclear integrity and their contribution to genome stability.
We focus on the following questions
What factors contribute to nuclear envelope integrity during cell division and interphase?
How do these factors cooperate to sense and execute a functional reformation response?
What are the consequences of loss of nuclear envelope integrity for genome stability and cancer genome evolution?
We perform mechanistic cell biological studies that include extensive live-cell microscopy, genetic manipulation, and proteomics approaches using non-transformed and cancer cell lines.