Generation, repair and replication of guanine oxidation products

Abstract

Guanine is the most readily oxidized of the four DNA bases, and guanine oxidation products cause G:C-T:A and G:C-C:G transversions through DNA replication. 8-Oxo-7,8-dihydroguanine (8-oxoG) causes G:C-T:A transversions but not G:C-C:G transversions, and is more readily oxidized than guanine. This review covers four major findings. (i) 2,2,4-Triamino-5(2H)-oxazolone (Oz) is produced from guanine and 8-oxoG under various oxidative conditions. Guanine is incorporated opposite Oz by DNA polymerases, except REV1. (ii) Several enzymes exhibit incision activity towards Oz. (iii) Since the redox potential of GG is lower than that of G, contiguous GG sequences are more readily oxidized by a one-electron oxidant than a single guanine, and OzOz is produced from GG in double-stranded DNA. Unlike most DNA polymerases, DNA polymerase ζ efficiently extends the primer up to full-length across OzOz. (iv) In quadruplex DNA, 3′-guanine is mainly damaged by one-electron oxidation in quadruplex DNA, and this damage depends on the highest occupied molecular orbital (HOMO). The oxidation products in quadruplex DNA are different from those in single-stranded or double-stranded DNA.

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…As summarized in the sections below, developments in the field of G4 ligand design have indeed permitted the design of several G4‐targeting agents to modify nucleic acid in a more selective manner, for example by metalation, alkylation or scission . Furthermore, since guanine is the most readily oxidized DNA base, it is not surprising that efforts have also been made to utilize G4 ligands as a mean to direct the site‐selective modification of nucleic acids in this way . The following sections explore the progress made in these areas.…”

“…For example, the syn conformation of 8oxo-guanosine may form Hoogsteen bonds to adenine rather than the usual Watson-Crick bonds to cytosine, leading to errors in DNA transcription. [128] Indeed, potential protective roles of G4s against such oxidative DNA damage have recently been explored. [150] Given the over-representation of guanine in G4 forming sequences and the ability to target these sequences with ligands, it is unsurprising that groups have made efforts to develop tools for G4-targeted oxidation.…”

“…Two possible pathways of oxidation of a guanine base are known. [128] Either singlet oxygen (generated by photosensitisation) may react directly with a guanine residue, generating 8-oxo-guanine 45 or spiroiminodihydantoin 46 (Scheme 4). Alternatively, the photoinduced metal-to-ligand charge transfer (MLCT) states of the complexes by may promote in photoinduced electron transfer (PET) and abstract an electron from the base to generate a guanine radi-Scheme 4.…”

“…Oxidation products of guanine generated by reaction with singlet oxygen. [128] cal cation (Scheme 5) leading to subsequent adduct formation between the oxidized base and one of the metal ligands to generate products of type 47 (Figure 21). The following sections consider strategies for G4-targeted oxidation that exploit these complementary reactivities.…”

DNA polymerase kappa counteracts inflammation‐induced mutagenesis in multiple organs of mice

“…Although 8‐oxo‐dG is less abundant than dG, it is more susceptible to oxidation than dG (Cui et al, ). The oxidation products include 2,2,4‐triamino‐5( 2H )‐oxazolone (Oz), guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) (Mangerich et al, ; Kino et al, ). Unlike 8‐oxo‐dG, which induces G:C to T:A transversion (Suzuki and Kamiya, ), these oxidation products can induce G:C to C:G transversion (Henderson et al, ; Kino et al, ; Mangerich et al, ; Kino et al, ).…”