Genetic identification and characterization of three genes that prevent accumulation of oxidative DNA damage in Drosophila adult tissues.

Reactive oxygen species generated in the process of energy production represent a major cause of oxidative DNA damage. Production of the oxidized guanine base, 8-oxo-guanine (8-oxoG), results in mismatched pairing with adenine and subsequently leads to G:C to T:A transversions after DNA replication. Our previous study demonstrated that Drosophila CG1795 encodes an ortholog of Ogg1, which is essential for the elimination of 8-oxoG. Moreover, the Drosophila ribosomal protein S3 (RpS3) possesses N-glycosylase activity that eliminates 8-oxoG in vitro. In this study, we show that RpS3 heterozygotes hyper-accumulate 8-oxoG in midgut cell nuclei after oxidant feeding, suggesting thatRpS3 is required for the elimination of 8-oxoG in Drosophila adults. We further showed that several muscle-aging phenotypes were significantly accelerated in RpS3 heterozygotes. Ogg1 is localized in the nucleus, while RpS3 is in the cytoplasm, closely associated with endoplasmic reticulum networks. Results of genetic analyses also suggest that these two proteins operate similarly but independently in the elimination of oxidized guanine bases from genomic DNA. Next, we obtained genetic evidence suggesting that CG42813 functions as the Drosophila ortholog of mammalian Mth1 in the elimination of oxidized dGTP (8-oxo-dGTP) from the nucleotide pool. Depletion of this gene significantly increased the number of DNA damage foci in the nuclei of Drosophila midgut cells. Furthermore, several aging-related phenotypes such as age-dependent loss of adult locomotor activities and accumulation of polyubiquitylated proteins in adult muscles were also significantly accelerated in CG42813-depleted flies. Lastly, we investigated the phenotype of adults depleted of CG9272, which encodes a protein with homology to mammalian Nth1 that is essential for the elimination of oxidized thymine. Excessive accumulation of oxidized bases was observed in the epithelial cell nuclei after oxidant feeding. In conclusion, three genes that prevent accumulation of oxidative DNA damage were identified in Drosophila.

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