Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents against Lung Cancer
Abstract
Oxygen-rich environments can create pro-mutagenic DNA lesions such as 8-oxoguanine (8-oxo-G) that can be misreplicated during translesion DNA synthesis (TLS). Our work has evaluated the pro-mutagenic behavior of 8-oxo- G by quantifying the ability of high-fidelity and specialized DNA polymerases to incorporate natural and modified nucleotides opposite this lesion. We have demonstrated that high-fidelity DNA polymerases (eukaryotic pol delta and bacteriophage T4 DNA polymerase) display error-prone tendencies when replicating 8-oxo-G, they display remarkably low efficiencies for TLS compared to normal DNA synthesis. In contrast, pol eta shows a combination of high efficiency and low fidelity when replicating 8-oxo-G. These combined properties are consistent with a pro- mutagenic role for pol eta when replicating this DNA lesion under cellular conditions. Studies with modified nucleotide analogs indicate that pol eta relies heavily on hydrogen-bonding interactions during normal and translesion synthesis. However, some nucleobase modifications including alkylation to the 06 and N2 position of guanine increase error-prone replication of 8-oxo-G. These results have identified two (2) nucleotide analogs that are efficiently and selectively utilized by pol eta. We tested the ability of the corresponding nucleoside analogs to act as anti-cancer agents by inhibiting the activity of pol eta when replicating damaged DNA induced by chemotherapeutic agents.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2015
- Accession Number
- AD1017278
Entities
People
- Anthony J. Bardis
Organizations
- Cleveland State University