Every time a human cell divides, it must dismantle and rebuild the protective membrane around its DNA—and the final sealing step is surprisingly fragile. This project investigates how a protein complex called ESCRT-III is switched on and off by chemical modifications to complete that seal. The problem is that cell division is well understood until the very end. Researchers know the signals that start mitosis, but they do not know how the cell coordinates the last moments of nuclear envelope repair. If that seal fails, the DNA is exposed to damaging molecules in the cell’s interior, which can cause mutations and disease. This is fundamental science. There is no immediate clinical application. The researcher will use genetic tools, protein analysis, and live-cell imaging to map exactly which phosphate groups attach to ESCRT-III and when. If successful, the work will reveal a basic timing mechanism that every dividing cell relies on. Past discoveries about how cells control their internal boundaries have led to insights into cancer, viral infection, and ageing—but those connections will only emerge once the core biology is understood.
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The nuclear envelope (NE) is a double membrane barrier which encloses the genome of eukaryotic cells, physically shielding the genetic material from the cytoplasmic environment. This creates a selective barrier that regulates the trafficking of proteins between the two compartments. During each mitosis, the NE is dismantled in prophase to allow the proper segregation of the duplicated chromosomes and then reassembled around the two nascent nuclei in late anaphase/telophase. Even though the circuitry of kinases/ phosphatase initiating and sustaining mitosis is well defined, how the latter mitotic events are fine-tuned to achieve a complete and timely NE sealing are still ill-understood. I will use a combination of genetic, proteomic, cellular biology and imaging approaches to shed light on how the ESCRT-III machinery is regulated by phosphorylation/dephosphorylation events and protein-protein interactions at sites of NE reformation during mitotic exit. Understanding the mechanistical aspects guiding nuclear reassembly will allow a better understanding of how mitotic exit events are coordinated in space and time to ensure a timely and functional nucleocytoplasmic compartmentalisation at every cell cycle. Moreover, NE defects are a known cause of disease, as chromatin exposure to the cytoplasmic milieu poses a threat to genome stability. Since ESCRT-III deregulation can lead to an impairment of NE integrity and eventually to a loss of nuclear compartmentalisation, a deeper understanding of how ESCRT-III proteins act in space and time could reveal not only new insights in the cellular mechanisms underlying pathology but also new therapeutical approaches.
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