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Abstract
Genomic DNA is constantly exposed to damaging agents, leading to diverse lesions. Cells employ repair and tolerance mechanisms, including translesion DNA synthesis (TLS), mediated by specialized polymerases. TLS can prevent cancer by accurate lesion bypass but may also promote carcinogenesis and chemoresistance through error-prone replication. This dissertation investigates TLS polymerase functions, focusing on newly discovered polymerase ν, identifies polymerases processing DNA–peptide cross-links, and explores polymerase κ as a therapeutic target by screening small-molecule inhibitors. Findings advance understanding of TLS in cancer development and resistance, offering strategies for novel combination therapies.