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 promutagenic 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 O6 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 h. We are currently testing the ability of the corresponding nucleoside analogs to act as anti-cancer agents that inhibit the activity of pol eta when replicating damaged DNA.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA621629
Entities
People
- Anthony J. Berdis
Organizations
- Cleveland State University