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The Role of Z-DNA in ZBP1-dependent Necroptosis Induced by the Curaxin

Student: Aleksandr Fedorov

Supervisor: Maria Poptsova

Faculty: Faculty of Computer Science

Educational Programme: Data Analysis for Biology and Medicine (Master)

Year of Graduation: 2021

ZBP1 is one of the key sensors of the innate immune system. Its role is not fully understood, but experimental data suggest that ZBP1 senses Z-nucleic acids using Zα domains and, depending on their concentration in the cell, initiate immune response. Ultimately, this leads to apoptosis, necroptosis, or pyroptosis of the cell. Сuraxin (CBL0137) is a new small molecule that intercalates DNA and causes large-scale changes in the three-dimensional chromatin structure. In particular, CBL0137 stimulates the formation of Z-DNA and leads to cell necroptosis. The latest experimental data confirm that ZBP1 protein is the key regulator of the observed necroptosis. This work is devoted to studying the role of Z-DNA in ZBP1-dependent necroptosis induced by the curaxin. The study shows that Z-DNA formed after treatment of cells with CBL0137 overlaps with the ZBP1 binding sites and is predominantly located in the 5'UTR of potentially active LINE-1 repeats. Active ZBP1 in the cell was found to significantly affect the distribution of the curaxin-induced Z-DNA. As the result of the conducted study, the role of Z-DNA in cellular immune response was confirmed: curaxin intercalates DNA and stimulates the B->Z conformational transition in the 5'UTR of intact LINE-1 repeats; ZBP1 binds to these repeats and initiates an immune response that leads to cell necroptosis.

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