Does membrane repair fail to alert the immune system to disease?

The cGAMP-synthase cGAS recognises microbial or self-DNA to activate STING and induce the release of pro-inflammatory molecules. But cytoplasmic DNA is also particularly abundant in cancer cells, under the form of genomic structures called ‘micronuclei’. These occur when lagging whole or fragments of chromosomes become compartmentalised by the nuclear envelope, and are the result of genomic instability or genotoxic stress. The NE of micronuclei is weak and spontaneously ruptures, exposing DNA to the cytoplasm, activating cGAS/STING and inducing inflammatory signals. But if micronuclei burst why they do not get repaired?

Nuclear envelope membranes are repaired by the ESCRT complex. We found that ESCRT is recruited but does not function at micronuclei (Willan et al, 8(5):29 Oncogenesis 2019). Here, ESCRT accumulates aberrantly, torqueing the NE, damaging underlying DNA and contributing to cGAS recruitment. Therefore, does membrane repair ‘malfunction’ at micronuclei represents an additional mechanism in the recognition of cytoplasmic DNA? We are looking for an enthusiastic and committed student to study specific molecular mechanisms that link the ESCRT pathway to inflammatory signalling in cancer cells. You will learn to use molecular biology and biochemistry techniques to study protein-protein interactions at the molecular scale together with dual colour fluorescence microscopy imaging on live and fixed cancer cells.

Your findings will have a major impact on our understanding of the wider role of cellular membranes integrity in health and disease. The knowledge generated will translate in novel approaches to diagnose and treat cancer.

If you hold a 2.1 honours masters level degree in Chemistry, Biochemistry or equivalent and are interested in studying a major biochemical mechanism at the basis of life, please get in touch with Dr Ciani ([Email Address Removed]).

**This is a self-funded project**