ROLE OF HUMAN NEI-LIKE DNA GLYCOSYLASES IN DNA REPAIR AND CANCER RESISTANCE
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Date
2024-02
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Nazarbayev University School of Engineering and Digital Sciences
Abstract
Individuals presenting with non-resectable and rapidly metastasizing tumors, including but not limited to breast and lung cancers, are commonly managed through the synergistic application of multi-agent chemotherapeutic regimens and ionizing radiation therapy. Chemotherapy and radiation therapy cause a type of DNA damage known as complex DNA damage (CDD). This includes large DNA adducts, links between DNA strands (interstrand DNA crosslinks), and clustered lesions, which are groups of damage that include double-strand breaks (DSBs). These complex damages are more intricate in their structure compared to individual, isolated lesions. (1).
Although CDDs constitute the minor proportion of total DNA damage that most anticancer agents inflict in cellular environments, its cytotoxicity is pronounced if left unrepaired. Whilst the sensitivity of cancer cells to chemotherapy and radiotherapy is usually acquired initially, but within three-to-twelve-month time, resistance to these therapies might be developed. Hence, the resistance of tumor cells to therapeutic intervention still largely confines the optimal efficacy of chemotherapy and radiotherapy for advanced cancers. The molecular mechanisms that underpin the intricate resistance in cancer are not fully elaborated. Among potential mechanisms, the activation of DNA repair pathways presents a compelling hypothesis. Importantly, the cross-resistance that tumor cells show with various DNA cross-linking agents after treatment with a single interstrand DNA crosslink-inducing agent would indicate upregulation of a definite DNA repair process on the part of the cells as an integral component of resistance to the cytotoxicity of interstrand DNA crosslinks in DNA (2).
Investigating the molecular mechanisms of DNA damage recognition by repair proteins could enhance our understanding of cellular DNA damage signaling and the coordination of repair processes.
In the present project, we propose to study repair of complex DNA damage in human cancer cells. The project aims to address following questions: (i) Whether there are unidentified repair activities present in cancer cells; (ii) What are the mechanisms of DNA repair coordination in human cancer cells and whether they involve the specific protein-protein interactions, multi-protein complexes and post-translational modifications; (iii) Whether the new post-replicative modification of DNA, discovered recently during our research collaboration, is involved in the removal of complex DNA damage and in the coordination of DNA repair pathways in cancer cells.
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Type of access: Gated, Nei-like DNA glycosylases, DNA repair, cancer resistance
Citation
Baiken, Y. (2024). Role of human Nei-like DNA glycosylases in DNA repair and cancer resistance. Nazarbayev University School of Engineering and Digital Sciences