Abstract
8-Oxoguanine, a major oxidized base lesion formed by reactive oxygen species, causes G to T transversion mutations or leads to cell death in mammals if it accumulates in DNA. 8-Oxoguanine can originate as 8-oxo-dGTP, formed in the nucleotide pool, or by direct oxidation of the DNA guanine base. MTH1, also known as NUDT1, with 8-oxo-dGTP hydrolyzing activity, 8-oxoguanine DNA glycosylase (OGG1) an 8-oxoG DNA glycosylase, and MutY homolog (MUTYH) with adenine DNA glycosylase activity, minimize the accumulation of 8-oxoG in DNA; deficiencies in these enzymes increase spontaneous and induced tumorigenesis susceptibility. However, different tissue types have different tumorigenesis susceptibilities. These can be reversed by combined deficiencies in the defense systems, because cell death induced by accumulation of 8-oxoG in DNA is dependent on MUTYH, which can be suppressed by MTH1 and OGG1. In cancer cells encountering high oxidative stress levels, a high level of 8-oxo-dGTP accumulates in the nucleotide pool, and cells therefore express increased levels of MTH1 in order to eliminate 8-oxo-dGTP. Suppression of MTH1 may be an efficient strategy for killing cancer cells; however, because MTH1 and OGG1 protect normal tissues from oxidative-stress-induced cell death, it is important that MTH1 inhibition does not increase the risk of healthy tissue degeneration.
Highlights
For living organisms, maintaining the integrity of genetic information, encoded in genomic DNA, and transmitting it precisely from cell to cell, as well as from parents to offspring is the most fundamental biological function
MutY homolog (MUTYH) has a functional proliferating cell nuclear antigen (PCNA)-binding motif [22], and we have shown that MUTYH repair of adenine incorporated opposite 8-oxoG in transfected plasmid
These results suggest that disruption of the Wnt/β-catenin signal transduction pathway, which leads to stabilization and accumulation of β-catenin in nuclei resulting in increased expression of c-Myc and cyclin D1 [43], is causal to oxidative-stress-induced tumorigenesis in the small intestines of Mutyh-KO
Summary
For living organisms, maintaining the integrity of genetic information, encoded in genomic DNA, and transmitting it precisely from cell to cell, as well as from parents to offspring is the most fundamental biological function. 8-Oxoguanine (8-oxoG) is one of the major oxidized bases in DNA or the nucleotide pool [3]. DNAs such as nuclear and mitochondrial genomes Disruption of these defense systems tends to increase susceptibility to spontaneous and induced tumorigenesis in mice. Among the guanine residues in various forms of nucleic acids, such as deoxyguanosine (dG), poly G, poly(dG–dC):poly(dG–dC) and denatured or native calf thymus DNA, the C-8 position of dG is the most effectively oxidized by ascorbic acid, generating 8-oxo-2'-deoxyguanosine (8-oxo-dG) (Figure 1A). It has been reported that 8-oxo-dGTP is present in the 0.2–2 μM range in the mitochondrial nucleotide pools of several rat tissues under normal conditions [9]. Because guanine bases in DNA can be directly oxidized to 8-oxoG by ROS, it is intriguing as to what extent insertion of 8-oxo-dGTP into. Regions with a high frequency of recombination and single nucleotide polymorphisms are preferentially located within chromosomal regions that have a high density of 8-oxo-dG [12]
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