Nuclear integrity and genome stability

Nuclear integrity and genome stability

Project leader: Coen Campsteijn

The nuclear envelope (NE) is the physical barrier that compartmentalizes the nucleus and protects the genome from damage. However, nuclear compartmentalization is compromised under various conditions, e.g. during open mitosis in many metazoans. Interphase cells also display reversible NE leaks, with increased frequency in cancer cells and cells with defects in their nuclear lamina (laminopathies). Micronuclei arising from chromosome segregation defects are also prone to irreversible rupture of their NE.

We have been aware of transient NE ruptures for some time, and mounting evidence highlights 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, and its contributions to the aetiology of cancer and laminopathies.

Central aim and research questions

The central aim 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?

Methodology

We perform mechanistic cell biological studies that include live-cell microscopy, genetic manipulation, and proteomics approaches using non-transformed and cancer cell lines.