ArticleProceedings of the National Academy of Sciences of the United States of America2008
8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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89 citing papers in PubMed, 129 citations in OpenAlex.
- Structural basis of transcription-coupled RNA damage by incorporation of oxidized ribonucleotides.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mistranslation suppresses mistranscription in eukaryotes.Nature communications · 2026Article
- Base excision repair within structure-forming repeat sequences and its impact on cancer and other diseases.NAR cancer · 2025Review
- Transcription fidelity and control of alternative splicing contribute to heat stress survival in Arabidopsis.The Plant cell · 2025Article
- The hidden costs of imperfection: transcription errors in protein aggregation diseases.Current opinion in genetics & development · 2025Review
- Transcription-Coupled Template Reconfiguration of 8-Oxoguanine for Error-Prone Transcription Revealed by Time-Resolved X-ray Crystallography and Molecular Dynamics.Journal of the American Chemical Society · 2025Article
- Oxidative genomic or genotoxic stress in neurodegeneration: Mechanisms and therapeutic avenues.AIMS neuroscience · 2025Review
- Linking Environmental Genotoxins to Neurodegenerative Diseases Through Transcriptional Mutagenesis.International journal of molecular sciences · 2024Review
- Transcript errors generate amyloid-like proteins in huwman cells.Nature communications · 2024Article
- Promoter dependent RNA polymerase II bypass of the epimerizable DNA lesion, Fapy•dG and 8-Oxo-2'-deoxyguanosine.Nucleic acids research · 2024Article
- Article
- Molecular Mechanism of RNA Polymerase II Transcriptional Mutagenesis by the Epimerizable DNA Lesion, Fapy·dG.Journal of the American Chemical Society · 2024Article
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- Transcriptional mutagenesis of α-synuclein caused by DNA oxidation in Parkinson's disease pathogenesis.Acta neuropathologica · 2023Article
- Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine.International journal of molecular sciences · 2023Review
- Evolutionary conservation of the fidelity of transcription.Nature communications · 2023Article
- The fidelity of transcription in human cells.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Detection of Oxidatively Modified Base Lesion(s) in Defined DNA Sequences by FLARE Quantitative PCR.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Article
- 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification.Experimental & molecular medicine · 2022Review
29 more citing papers are in PubMed but not listed here.
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4 authors at 2 institutions in 2 countries.
Funding
Abstract
8-Oxoguanine (8OG) is efficiently bypassed by RNA polymerases in vitro and in bacterial cells in vivo, leading to mutant transcripts by directing incorporation of an incorrect nucleotide during transcription. Such transcriptional mutagenesis (TM) may produce a pool of mutant proteins. In contrast, transcription-coupled repair safeguards against DNA damage, contingent upon the ability of lesions to arrest elongating RNA polymerase. In mammalian cells, the Cockayne syndrome B protein (Csb) mediates transcription-coupled repair, and its involvement in the repair of 8OG is controversial. The DNA glycosylase Ogg1 initiates base excision repair of 8OG, but its influence on TM is unknown. We have developed a mammalian system for TM in congenic mouse embryonic fibroblasts (MEFs), either WT or deficient in Ogg1 (ogg(-/-)), Csb (csb(-/-)), or both. This system uses expression of the Ras oncogene in which an 8OG replaces guanine in codon 61. Repair of 8OG restores the WT sequence; however, bypass and misinsertion opposite this lesion during transcription leads to a constitutively active mutant Ras protein and activation of downstream signaling events, including increased phosphorylation of ERK kinase. Upon transfection of MEFs with replication-incompetent 8OG constructs, we observed a marked increase in phospho-ERK in ogg(-/-) and csb(-/-)ogg(-/-) cells at 6 h, indicating persistence of the lesion and the occurrence of TM. This effect is absent in WT and csb(-/-) cells, suggesting rapid repair. These studies provide evidence that 8OG causes TM in mammalian cells, leading to a phenotypic change with important implications for the role of TM in tumorigenesis.
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