MEMBRANE REPAIR BY THE ESCRT COMPLEX
The endosomal sorting complex required for transport (ESCRT) is an ancient and highly conserved heteromultimeric protein complex that drives constriction and scission of small membrane necks that are filled with cytosol. This function of ESCRT occurs in many fundamental processes of our cells, such as endosome maturation, autophagosome closure, cytokinesis and repair of damaged plasma membrane as well as damaged lysosomes. ESCRT is also crucial for the maintenance of an intact nuclear envelope. Our group has shown that ESCRT is recruited to small holes of the nascent nuclear envelope during anaphase of human cells. Here, ESCRT coordinates the disassembly of mitotic spindle microtubules with membrane sealing. Similarly, ESCRT was found to seal ruptures of the nuclear envelope in interphase cells.
DEFECTIVE NUCLEAR ENVELOPES IN CANCER
Cancer cells can contain micronuclei, aberrant cytosolic DNA structures that stem from uncontrolled cell division, high degree of DNA damage, and genotoxic treatments commonly used in the clinic. Like the cell nucleus, also micronuclei are surrounded by their envelope. However, ruptures at the micronuclear envelope are rarely repaired. We surprisingly discovered that the ESCRT complex, while being essential for repair of the nuclear envelope, is unable to repair ruptures at the envelope surrounding micronuclei. Instead, ESCRT "loses control" and causes severe membrane defects to the point of micronuclei catastrophe.This in turn initiates immune/inflammatory responses as well as severe chromosome damage culminating in complex genomic rearrangements that drive tumorigenesis and resistance to therapy.
Electron Microscopy Tomogram and modeling of a catastrophic micronucleus (This image was acquired and reconstructed by Dr. Sebastian Schultz
