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Protein S-nitrosation as a trigger for DNA leakage from the nucleus: in the quest for a mechanism.

Preludium program. National Science Centre. 
PI – Aleksandra Kopacz (to be completed in 2023).

In eukaryotes, DNA is generally confined to the cell nucleus and mitochondria (and chloroplast in case of plants). Its presence in the cytosol is abnormal and may indicate pathogen infection or excessive DNA damage. DNA sensors shall detect it to launch proper downstream signalling, which includes secretion of interferon-gamma to attract immune cell, intrinsical inhibition of cell division or, in case of extreme damage, apoptosis. Our preliminary data indicate that inhibition of denitrosating enzyme GSNOR promotes the release of DNA into the cytoplasm, and triggers enhanced proliferation in primary human endothelial cells. The reason for DNA release from the nucleus and its mechanism remains unidentified. Additionally, we observe protein aggregates' colocalisation with the cytoplasmic DNA. We suspect that protein aggregates serve as a signal for clearance of cytoplasmic DNA and initiation of proper cellular signalling, which is hampered and ineffective in cells exhibiting excessive S-nitrosation. Basing on our preliminary data, we hypothesise that: S-nitrosation not only perturbs DNA repair and nuclear integrity triggering the release of DNA into the cytoplasm but also disrupts its clearance and downstream signalling. It enables the further proliferation of dysfunctional cells, what, overall, may promote genetic instability and oncogenesis. Our proposal aims to verify this hypothesis. Using a model of primary human endothelial cells, in which we will manipulate the level of S-nitrosation, we will answer four questions: i) Why does S-nitrosation trigger DNA leakage from the nucleus? ii) Does protein aggregation play a role in the clearance of cytoplasmic DNA? If so, how? iii) Why do the cells not undergo apoptosis or cell cycle arrest when DNA leaks into cytoplasm? iv) Do such cells have oncogenic potential? The answers to these questions can point to the neglected role of S-nitrosation in governing the endothelial cell fate and in DNA compartmentalisation along with maintenance of its stability.

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