Synergistic effects on mutagenicity of tandem lesions containing 8-oxo-7,8-dihydro-2′-deoxyguanosine or Fapy•dG flanked by a 3′ 5-formyl-2′-deoxyuridine in human cells

Bacurio, Jan Henric T.; Gao, Shijun; Yang, Haozhe; Basu, Ashis K.; Greenberg, Marc M.

doi:10.1016/j.dnarep.2023.103527

Cited by 5 publications

(22 citation statements)

References 57 publications

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“…For both 8-OxodGuo and 5′-8-OxodGuo-5-fdU, G → T transversions were the only mutations at the 8-OxodGuo site. Contrary to the low level of T → G and T → A tranversions also detected at the 5-fdU site in human cells, 38 no other mutations occurred at this lesion in E. coli. G → T transversions increased in hPol ιand hPol κ-deficient HEK 293T cells compared to WT cells, 38 as they did in the absence of SOS induction in Pol IIand Pol IV-deficient E. coli relative to WT.…”

Section: ■ Discussioncontrasting

confidence: 79%

“…Analysis of progeny phage was carried out by oligonucleotide hybridization, followed by DNA sequencing as described. 24,38 ■ RESULTS TLS Efficiency and Mutagenicity of Isolated 8-OxodGuo, Fapy•dG, and 5-fdU. We determined the replication properties of an isolated 8-OxodGuo and Fapy•dG in CG*T and 5-fdU in GT*G sequence context (i.e., 5′-GTG CG*T GTT TGT-3′ and 5′-GTG CGT* GTT TGT-3′) in E. coli AB1157 strain (Table 1).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…35 In a recent study we showed that these tandem lesions are more mutagenic than the respective isolated lesions in human cells. 38 As codon 273 of the p53 tumor suppressor gene is a mutational hot spot found in human cancer, 40−42 the tandem lesions were examined in the context of codons 272−275, 5′-GTG CG*T* GTT TGT-3′, where G*T* represents the tandem lesions and codon 273 is underscored. In the current study, we investigated the mutagenicity of these two tandem lesions in E. coli within the same sequence context.…”

Section: ■ Introductionmentioning

confidence: 99%

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8-OxodGuo and Fapy•dG Mutagenicity in Escherichia coli Increases Significantly when They Are Part of a Tandem Lesion with 5-Formyl-2′-deoxyuridine

Dasgupta,

Gao,

Yang

et al. 2024

Chem. Res. Toxicol.

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Tandem lesions, which are defined by two or more contiguously damaged nucleotides, are a hallmark of ionizing radiation. Recently, tandem lesions containing 5-formyl-2′-deoxyuridine (5-fdU) flanked by a 5′-8-OxodGuo or Fapy•dG were discovered, and they are more mutagenic in human cells than the isolated lesions. In the current study, we examined replication of these tandem lesions in Escherichia coli. Bypass efficiency of both tandem lesions was reduced by 30−40% compared to the isolated lesions. Mutation frequencies (MFs) of isolated 8-OxodGuo and Fapy•dG were low, and no mutants were isolated from replication of a 5-fdU construct. The types of mutations from 8-OxodGuo were targeted G → T transversion, whereas Fapy•dG predominantly gave G → T and G deletion. 5′-8-OxodGuo-5-fdU also gave exclusively G → T mutation, which was 3-fold and 11-fold greater, without and with SOS induction, respectively, compared to that of an isolated 8-OxodGuo. In mutY/mutM cells, the MF of 8-OxodGuo and 5′-8-OxodGuo-5-fdU increased 13-fold and 7fold, respectively. The MF of 5′-8-OxodGuo-5-fdU increased 2-fold and 3-fold in Pol II-and Pol IV-deficient cells, respectively, suggesting that these polymerases carry out largely error-free bypass. The MF of 5′-Fapy•dG-5-fdU was similar without (13 ± 1%) and with (16 ± 2%) SOS induction. Unlike the complex mutation spectrum reported earlier in human cells for 5′-Fapy•dG-5-fdU, with G → T as the major type of errors, in E. coli, the mutations were predominantly from deletion of 5-fdU. We postulate that removal of adenine-incorporated opposite 8-OxodGuo by Fpg and MutY repair proteins is partially impaired in the tandem 5′-8-OxodGuo-5-fdU, resulting in an increase in the G → T mutations, whereas a slippage mechanism may be operating in the 5′-Fapy•dG-5-fdU mutagenesis. This study showed that not only are these tandem lesions more mutagenic than the isolated lesions but they may also exhibit different types of mutations in different organisms.

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Section: ■ Discussioncontrasting

confidence: 79%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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8-OxodGuo and Fapy•dG Mutagenicity in Escherichia coli Increases Significantly when They Are Part of a Tandem Lesion with 5-Formyl-2′-deoxyuridine

Dasgupta,

Gao,

Yang

et al. 2024

Chem. Res. Toxicol.

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“…The replications of 8-OxoG-5fU and Fapy•G-5fU tandem lesions in HEK 293T cells with or without deficiency of bypass polymerases were examined [60]. The local sequence of the tandem lesions encompasses the 273 codon of the p53 gene, a mutational hot-spot in human cancer.…”

Section: -Oxog-fu and Fapy•g-fumentioning

confidence: 99%

Mutagenesis and Repair of γ-Radiation- and Radical-Induced Tandem DNA Lesions

Basu,

Colis,

Bacurio

2024

DNA

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Ionizing radiation induces many different types of DNA lesions. But one of its characteristics is to produce complex DNA damage, of which tandem DNA damage has received much attention, owing to its promise of distinctive biological properties. Oxidative stresses in response to inflammation in tissues and metal-catalyzed reactions that result in generation of radicals also form these DNA lesions. In this minireview, we have summarized the formation of the tandem lesions as well as the replication and repair studies carried out on them after site-specific synthesis. Many of these lesions are resistant to the traditional base excision repair, so that they can only be repaired by the nucleotide excision repair pathway. They also block DNA replication and, when lesion bypass occurs, it may be significantly error-prone. Some of these tandem DNA lesions may contribute to ageing, neurological diseases, and cancer.

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“…Fapy·dG has been shown to be equally, if not more, mutagenic as 8-OxodGuo in mammalian cells, yet no information is available regarding its bypass by an RNA polymerase. ,– Herein, we investigate the molecular mechanism of RNA polymerase II (Pol II) transcriptional mutagenesis induced by Fapy·dG in the transcribed DNA strand by using combined biochemical and structural approaches.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of RNA Polymerase II Transcriptional Mutagenesis by the Epimerizable DNA Lesion, Fapy·dG

Gao,

Hou,

et al. 2024

J. Am. Chem. Soc.

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Oxidative DNA lesions cause significant detrimental effects on a living species. Two major DNA lesions resulting from dG oxidation, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-OxodGuo) and formamidopyrimidine (Fapy•dG), are produced from a common chemical intermediate. Fapy•dG is formed in comparable yields under oxygen-deficient conditions. Replicative bypass of Fapy•dG in human cells is more mutagenic than that of 8-OxodGuo. Despite the biological importance of transcriptional mutagenesis, there are no reports of the effects of Fapy•dG on RNA polymerase II (Pol II) activity. Here we perform comprehensive kinetic studies to investigate the impact of Fapy•dG on three key transcriptional fidelity checkpoint steps by Pol II: insertion, extension, and proofreading steps. The ratios of error-free versus error-prone incorporation opposite Fapy•dG are significantly reduced in comparison with undamaged dG. Similarly, Fapy•dG:A mispair is extended with comparable efficiency as that of the error-free, Fapy•dG:C base pair. The αand β-configurational isomers of Fapy•dG have distinct effects on Pol II insertion and extension. Pol II can preferentially cleave error-prone products by proofreading. To further understand the structural basis of transcription processing of Fapy•dG, five different structures were solved, including Fapy•dG template-loading state (apo), error-free cytidine triphosphate (CTP) binding state (prechemistry), error-prone ATP binding state (prechemistry), error-free Fapy•dG:C product state (postchemistry), and error-prone Fapy•dG:A product state (postchemistry), revealing distinctive nucleotide binding and product states. Taken together, our study provides a comprehensive mechanistic framework for better understanding how Fapy• dG lesions impact transcription and subsequent pathological consequences.

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Synergistic effects on mutagenicity of tandem lesions containing 8-oxo-7,8-dihydro-2′-deoxyguanosine or Fapy•dG flanked by a 3′ 5-formyl-2′-deoxyuridine in human cells

Cited by 5 publications

References 57 publications

8-OxodGuo and Fapy•dG Mutagenicity in Escherichia coli Increases Significantly when They Are Part of a Tandem Lesion with 5-Formyl-2′-deoxyuridine

8-OxodGuo and Fapy•dG Mutagenicity in Escherichia coli Increases Significantly when They Are Part of a Tandem Lesion with 5-Formyl-2′-deoxyuridine

Mutagenesis and Repair of γ-Radiation- and Radical-Induced Tandem DNA Lesions

Molecular Mechanism of RNA Polymerase II Transcriptional Mutagenesis by the Epimerizable DNA Lesion, Fapy·dG

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