The calculated stability of DNA duplexes containing an oxidized guanine lesion pairing with guanine

Katsuhito Kino,Taihei Watanabe,Hiroshi Miyazawa,Masayo Suzuki,Eriko Asada,Takanobu Kobayashi,Masayuki Morikawa

doi:10.3390/ecsoc-17-e011

Abstract

DNA is damaged by various oxidative stresses. Oxidized DNA can increase mutations and the risk of cancer. Guanine is highly sensitive to several oxidative stresses due to its low oxidation potential. It is known that 2,2,4-triamino-5(2H)-oxazolone (Oz), iminoallantoin (Ia) and spiroiminodihydantoin (Sp) are oxidized guanine lesions. These oxidized bases can be paired with guanine and cause G:C-C:G transversions. Although our previous results showed more effective incorporation of guanine opposite Oz compared to that opposite Ia or Sp (K. Kino et al., ChemBioChem, 2009), Oz:G base pair was less stable than Ia:G or Sp:G base pair by ab initio calculation (M. Suzuki et al., Molecules, 2012). Oz:G forms two hydrogen bonds and is planar, while Ia:G and Sp:G have three hydrogen bonds and are nonplanar. This difference can be due to the fact that Ia:G and Sp:G contain a sp3 carbon but not Oz:G. Since stacking planar base pairs in DNA significantly enhances the stability of DNA duplex, we investigate whether the stability of DNA duplex containing the oxidized lesion can be accounted for by the stacking effect in this study. The structure of DNA duplex containing Oz:G was the most stable. This our data agreed with the previous results that translesion synthesis across Oz was more effective than Ia or Sp.

Highlights

Various oxidative stresses-induced alterations in genomic information have been involved in carcinogenesis, aging, and other diseases
The DNA polymerase β (Pol β) –DNA complexes containing an G:X (X = C, Oz, S-Ia, R-Ia, S-Sp or R-Sp) base pair were built by modification of the structure in PDB
ΔE1 of Oz was less stable than ΔE1 of R-Ia in our calculated data, which can not explain the previous experimental results that translesion synthesis past Oz is more efficient than that past Ia [4]

Summary

Introduction

Various oxidative stresses-induced alterations in genomic information have been involved in carcinogenesis, aging, and other diseases. Since guanine has the lowest oxidation potential among the four bases, guanine is highly sensitive to several oxidative stresses. It is known that 8-oxo-7,8-dihydroguanine (8-oxoG) is a major oxidation product of guanine under various oxidative conditions (Figure 1). Since 8-oxoG can be paired with adenine but not guanine, 8-oxoG:A base pairs cause G:C-T:A transversions [2]; that is, it is assumed that G:C-C:G transversions are cause by the other oxidation products of guanine. 2,5-Diamino-4H-imidazol-4-one (Iz), an oxidation product of guanine and 8-oxoG [3], is hydrolyzed to 2,2,4-triamino-5(2H)-oxazolone (Oz) under physiological conditions (Figure 1) [3]. We previously predicted that the G:Oz base pair is planar and has two hydrogen bonds (Figure 2) [4]

Methods

Results

Conclusion