Accession Number:

ADA621629

Title:

Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents Against Lung Cancer

Descriptive Note:

Annual rept. 20 Sep 2013-19 Sep 2014

Corporate Author:

CLEVELAND STATE UNIV OH

Personal Author(s):

Report Date:

2014-10-01

Pagination or Media Count:

43.0

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.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE