The Role of CIZ1 in the Response to DNA Replication Stress

Toth, Hanna and Copeland, Nikki and Kotsantis, Panagiotis (2025) The Role of CIZ1 in the Response to DNA Replication Stress. Masters thesis, Lancaster University.

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Abstract

Cancer is one of the leading causes of morbidity and mortality worldwide, posing a significant burden on healthcare systems. Understanding the function of proteins that are aberrantly expressed in cancer may inform the development of more targeted therapeutic strategies. CIZ1 (Cip1 interacting zinc finger protein 1) is a nuclear matrix protein with an important role in the G1/S transition of the cell cycle. Its role as an oncogene has been well established, however a few studies have also reported a potential tumour suppressor role for this protein. This research project aims to explore the role of CIZ1 in DNA replication stress and DNA repair to explore its tumour suppressor function. In vitro experiments with CIZ1 knockout (KO) and wildtype (WT) mouse embryonic fibroblasts were conducted, inducing DNA replication stress using hydroxyurea. Cell viability, cell cycle, and DNA damage repair pathway response were analysed after DNA replication stress induction and recovery. The findings of this research indicate that CIZ1 KO cells show lower rates of apoptosis in response to DNA replication stress than WT, increased cell cycle arrest and slower proliferation than WT. CIZ1 KO cells also had more micronuclei than WT and showed increased nuclear size after DNA replication stress induction. The DNA damage repair pathways in CIZ1 KO cells also appeared to be impaired. Overall, this research suggests that CIZ1 potentially has a role in the response to DNA replication stress and DNA damage signalling, indicating a modulatory rather than essential role in these processes. Future work is necessary to further understand the tumour suppressor role of CIZ1.